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1
Zhang, Jing, Shouguo Huang, Lini Quan, Qiu Meng, Haiyan Wang, Jie Wang e Jin Chen. "Determination of Potential Therapeutic Targets and Prognostic Markers of Ovarian Cancer by Bioinformatics Analysis". BioMed Research International 2021 (19 marzo 2021): 1–13. http://dx.doi.org/10.1155/2021/8883800.
Abstract (sommario):
This study is to study the expression of CXCRs in ovarian cancer tissues and their value in prognosis. The expressions of CXCR1-CXCR7 mRNA between ovarian tumor tissues and normal tissues and in different pathological types of ovarian tumor tissues were compared by ONCOMINE online tool. The relationship between the expression of CXCRs and clinical pathological staging was studied by GEPIA. Kaplan-Meier plotter online tool was used to analyze prognosis. Finally, GO and KEGG analyses and protein interaction network analysis were performed for CXCRs by the DAVID software to predict their function, and cBioPortal was used to identify the key functional genes. The expression of CXCR3/4/7 mRNA in ovarian cancer tissues was higher than that in normal ovarian tissues, and the expression of CXCR4 was the highest ( fold change = 306.413 , P < 0.05 ). The expression of CXCR1/2/3/4/7 mRNA in different pathological types of ovarian tumors was significantly different ( P < 0.05 ). Only CXCR5 expression level was associated with tumor staging. Survival analysis showed that high CXCR7 mRNA expression and low CXCR5/6 expression were associated with the shortening of overall survival. High CXCR4/7 expression and low CXCR5/6 expression were associated with the shortening of progression-free survival. High CXCR2/4 expression and low CXCR5/6 expression were closely related to the shortening of postprogressing survival. Protein interaction network analysis showed that GNB1, PTK2, MAPK1, PIK3CA, GNB4, GNA11, KNG1, and ARNT proteins were closely related to the CXC receptor family. CXCR3/4/7 are potential therapeutic targets, and CXCR2/4/5/6/7 are new markers for the prognosis of ovarian cancer.
2
Doroshenko, Tatyana, Yuri Chaly, Valery Savitskiy, Olga Maslakova, Anna Portyanko, Irina Gorudko e Nikolai N. Voitenok. "Phagocytosing neutrophils down-regulate the expression of chemokine receptors CXCR1 and CXCR2". Blood 100, n. 7 (1 ottobre 2002): 2668–71. http://dx.doi.org/10.1182/blood.100.7.2668.
Abstract (sommario):
CXC chemokines play a central role in regulation of neutrophil activation and chemotaxis. Because the chemotactic responses of neutrophils are impaired after phagocytosis, we explored the effect of phagocytic stimuli on the expression of interleukin-8 (IL-8) receptors, CXCR1 and CXCR2, in human neutrophils. After phagocytosis of opsonized yeast, the expression of CXCR1 and CXCR2 was substantially down-regulated and was accompanied by reduced Ca++responses to corresponding ligands, IL-8 and neutrophil-activating peptide–2 (NAP-2). The levels of CXCR1 and CXCR2 mRNA were constant during phagocytic stimulation of neutrophils. Confocal microscopy revealed that CXCR reduction was not via internalization. Metalloproteinase inhibitor, 1,10-phenantroline, prevented the reduction of CXCRs induced by phagocytosis, indicating that proteolytic degradation may be responsible for down-regulation. These observations suggest that down-regulation of CXCR expression may substantially reduce the responsiveness of phagocytosing neutrophils to CXC chemokines.
3
Konrad, F. M., e J. Reutershan. "CXCR2 in Acute Lung Injury". Mediators of Inflammation 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/740987.
Abstract (sommario):
In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR) 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR+chemokines, including MIP-2, KC (rodents) and IL-8 (human). Since multiple ELR+CXC chemokines act on both receptors—CXCR1 and CXCR2—a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target.
4
Feniger-Barish, Rotem, Dan Belkin, Alon Zaslaver, Shira Gal, Mally Dori, Maya Ran e Adit Ben-Baruch. "GCP-2–induced internalization of IL-8 receptors: hierarchical relationships between GCP-2 and other ELR+-CXC chemokines and mechanisms regulating CXCR2 internalization and recycling". Blood 95, n. 5 (1 marzo 2000): 1551–59. http://dx.doi.org/10.1182/blood.v95.5.1551.005a36_1551_1559.
Abstract (sommario):
The chemotactic potencies of ELR+-CXC chemokines during acute inflammation are regulated by their binding affinities and by their ability to activate, desensitize, and internalize their specific receptors, CXCR1 and CXCR2. To gain insight into the fine mechanisms that control acute inflammatory processes, we have focused in this study on the highly potent ELR+-CXC chemokine Granulocyte Chemotactic Protein 2 (GCP-2), and on its ability to control the cell surface expression of CXCR1 and CXCR2. Although GCP-2 has been considered an effective ligand for both CXCR1 and CXCR2, our findings demonstrated that it was a potent inducer of CXCR2 internalization only. A functional hierarchy was shown to exist between GCP-2 and 2 other ELR+-CXC chemokines, IL-8 and NAP-2, in their abilities to induce CXCR1 and CXCR2 internalization, according to the following: IL-8 > GCP-2 > NAP-2. By the use of pertussis toxin (PTx), it was demonstrated that the actual events of Gi-coupling to CXCR2 do not have a major role in the regulation of its internalization. Rather, CXCR2 internalization was shown to be negatively controlled by induction of signaling events, as indicated by the promotion of CXCR2 internalization following exposure to wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3 kinases and PI4 kinases. Furthermore, our results suggest that rab11+-endosomes participate in the trafficking of CXCR2 through the endocytic pathway, to eventually allow its recycling back to the plasma membrane. To conclude, our findings shed light on the interrelationships between GCP-2 and other ELR+-CXC chemokines, and determine the mechanisms involved in the regulation of GCP-2–induced internalization and recycling of CXCR2.
5
Smithson, Alex, Maria Rosa Sarrias, Juanjo Barcelo, Belen Suarez, Juan Pablo Horcajada, Sara Maria Soto, Alex Soriano et al. "Expression of Interleukin-8 Receptors (CXCR1 and CXCR2) in Premenopausal Women with Recurrent Urinary Tract Infections". Clinical Diagnostic Laboratory Immunology 12, n. 12 (dicembre 2005): 1358–63. http://dx.doi.org/10.1128/cdli.12.12.1358-1363.2005.
Abstract (sommario):
ABSTRACT The migration of neutrophils through infected tissues is mediated by the CXC chemokines and its receptors (CXCR1 and CXCR2). It has been proposed that a CXCR1 deficiency could confer susceptibility to acute pyelonephritis in children. The objective of the study is to assess the surface expression of CXCR1 and CXCR2 and the existence of polymorphisms in the CXCR1 gene in premenopausal women with recurrent urinary tract infections. The study included 20 premenopausal women with recurrent urinary infections, with normal urinary tracts, and without diseases potentially associated with relapsing urinary infections and 30 controls without previous urinary infections. The levels of CXCR1 and CXCR2 expression on neutrophils were measured and analyzed by flow cytometry by measuring the mean fluorescence intensity (MFI) channel. The promoter and coding regions of the CXCR1 gene were analyzed for the presence of polymorphisms by a sequence-based typing method. Patients with recurrent urinary tract infections exhibited median levels of CXCR1 expression, determined from MFI values, similar to those of the controls. The analysis of CXCR2 showed that patients with recurrent urinary infections had lower median levels of expression, determined from the MFI values, than the controls (P = 0.002, Mann-Whitney U test). No polymorphisms were detected at the promoter or at the exon 1 region of the CXCR1 gene either in the patients or in the controls. Polymorphisms were detected at the exon 2 of CXCR1, but their frequencies did not differ between patients and controls. We have found a low level of CXCR2 expression in patients with recurrent urinary tract infections. These results suggest that a low level of CXCR2 expression may increase the susceptibilities of premenopausal women to urinary tract infections.
6
Molczyk, Caitlin, e Rakesh K. Singh. "CXCR1: A Cancer Stem Cell Marker and Therapeutic Target in Solid Tumors". Biomedicines 11, n. 2 (16 febbraio 2023): 576. http://dx.doi.org/10.3390/biomedicines11020576.
Abstract (sommario):
Therapy resistance is a significant concern while treating malignant disease. Accumulating evidence suggests that a subset of cancer cells potentiates tumor survival, therapy resistance, and relapse. Several different pathways regulate these purported cancer stem cells (CSCs). Evidence shows that the inflammatory tumor microenvironment plays a crucial role in maintaining the cancer stem cell pool. Typically, in the case of the tumor microenvironment, inflammatory pathways can be utilized by the tumor to aid in tumor progression; one such pathway is the CXCR1/2 pathway. The CXCR1 and CXCR2 receptors are intricately related, with CXCR1 binding two ligands that also bind CXCR2. They have the same downstream pathways but potentially separate roles in the tumor microenvironment. CXCR1 is becoming more well known for its role as a cancer stem cell identifier and therapeutic target. This review elucidates the role of the CXCR1 axis as a CSC marker in several solid tumors and discusses the utility of CXCR1 as a therapeutic target.
7
Ngo, Hai, Evdoxia Hatjiharissi, Xavier Leleu, Judith Runnels, Anne-Sophie Moreau, Xiaoying Jia, Garrett O’Sullivan et al. "The CXCR4/SDF-1 Axis Regulates Migration and Adhesion in Waldenstrom Macroglobulinemia." Blood 108, n. 11 (1 novembre 2006): 2418. http://dx.doi.org/10.1182/blood.v108.11.2418.2418.
Abstract (sommario):
Abstract Background: Waldenstrom Macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow (BM), and lymphadenopathy in 20% of the patients, implying continuous trafficking of WM cells into and out of the BM and lymph nodes. The normal process of B-cell homing is regulated by cytokines, chemokines, and adhesion molecules. One of the most extensively studied chemokines in migration is stromal derived factor SDF-1 and its receptor CXCR4. Here we study the role of chemokine receptors, and the SDF-1/CXCR4 axis on migration and adhesion in WM. Methods: Flow cytometry for CXC and CC chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CCR2, CCR4, CCR5, CCR6 and CCR7), and adhesion molecules (VLA-4 and LFA-1) on WM cell lines (BCWM.1 and WM-WSU) and patient samples was performed. Migration was determined using the transwell migration assay (Costar, NY). Cells were placed in the upper chambers of the migration assay with 1% FCS medium in the presence of serial concentrations of SDF-1 in the lower chambers. After 4 hours of incubation, cells that migrated to the lower chambers were counted. Similarly, adhesion was determined using an adhesion assay (EMD Biosciences, San Diego, CA) with 96-well plated coated with fibronectin. Immunoblotting for proteins downstream of CXCR4 was performed. The CXCR4 inhibitor AMD3100 (10–100uM, Sigma, MO) and Gi protein inhibitor pertussis toxin PTX (10–200ng/ml, Sigma, MO) were used to inhibit CXCR4 signaling. Results: The following chemokine receptors were expressed on patient CD19+WM cells with over 30% expression: CXCR1 (mean 60%), CXCR2 (mean 47%), CXCR4 (mean 47%), CXCR5 (mean 69%), CCR4 (mean 54%) and CCR6 (mean 61%). Similar expression was observed on WM cell lines. We next determined the effect of SDF-1 on migration and signaling pathways in WM. SDF-1 (10–100nM) induced migration in a bell-shaped curve with 30nM inducing maximum migration (110% compared to control). SDF-1 30nM induced a rapid activation of signaling pathways downstream of CXCR4 including pERK1/2, pAKT, and pPKC at 1 min, with maximum activation at 5min. The CXCR4 inhibitor AMD3100 inhibited migration of BCWM.1 in the presence of 30nM SDF-1, with AMD3100 10uM inhibiting migration at 59% of control, and 20 to 50uM leading to a plateau in inhibition of migration at 54% of control. AMD3100 inhibited pERK and pPKC activation, downstream of CXCR4 in a dose-dependent fashion. Similar results were observed using PTX, with inhibition of migration of WM cells at 50% compared to control. To determine the role of SDF-1 on adhesion, we first demonstrated that WM cells from patients and cell lines expressed high levels of surface VLA-4 expression (mean 95% surface expression). WM cells had an increase in adhesion to fibronectin (VLA-4 ligand) compared to BSA control. AMD3100 10uM inhibited adhesion to fibronectin (63 % of control), indicating that the SDF-1/CXCR4 axis regulates adhesion. Conclusion: CXCR4 is highly expressed on WM cells and regulates migration and adhesion, indicating a potential role in regulating WM trafficking into the BM and lymph nodes. These studies provide the preclinical framework to study CXCR4 inhibitors in the regulation of homing and adhesion in WM.
8
Khandaker, Masud H., Luoling Xu, Rahbar Rahimpour, Gordon Mitchell, Mark E. DeVries, J. Geoffrey Pickering, Sharwan K. Singhal, Ross D. Feldman e David J. Kelvin. "CXCR1 and CXCR2 Are Rapidly Down-Modulated by Bacterial Endotoxin Through a Unique Agonist-Independent, Tyrosine Kinase-Dependent Mechanism". Journal of Immunology 161, n. 4 (15 agosto 1998): 1930–38. http://dx.doi.org/10.4049/jimmunol.161.4.1930.
Abstract (sommario):
Abstract The expression of the seven-transmembrane domain chemokine receptors CXCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattractant IL-8 and a number of closely related CXC chemokines. In the present study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 expression on human neutrophils. Treating neutrophils with LPS reduced IL-8R expression to 55 ± 5% of the control within 30 min and to 23 ± 2% within 1 h of stimulation. Furthermore, this down-modulation could not be attributed to increased concentrations of IL-8, TNF-α, or IL-1β, since ELISA studies indicated that LPS-stimulated neutrophils did not release detectable amounts of these proteins before 2 h poststimulation. The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, indicating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyperphosphorylation of the protein TK p72syk. Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect. These studies provide the first evidence of an agonist-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.
9
Vacchini, Alessandro, Anneleen Mortier, Paul Proost, Massimo Locati, Mieke Metzemaekers e Elena Borroni. "Differential Effects of Posttranslational Modifications of CXCL8/Interleukin-8 on CXCR1 and CXCR2 Internalization and Signaling Properties". International Journal of Molecular Sciences 19, n. 12 (27 novembre 2018): 3768. http://dx.doi.org/10.3390/ijms19123768.
Abstract (sommario):
CXCL8 or interleukin (IL)-8 directs neutrophil migration and activation through interaction with CXCR1 and CXCR2 that belong to the family of G protein-coupled receptors (GPCRs). Naturally occurring posttranslational modifications of the NH2-terminal region of CXCL8 affect its biological activities, but the underlying molecular mechanisms are only partially understood. Here, we studied the implications of site-specific citrullination and truncation for the signaling potency of CXCL8. Native CXCL8(1-77), citrullinated [Cit5]CXCL8(1-77) and the major natural isoform CXCL8(6-77) were chemically synthesized and tested in internalization assays using human neutrophils. Citrullinated and truncated isoforms showed a moderately enhanced capacity to induce internalization of CXCR1 and CXCR2. Moreover, CXCL8-mediated activation of Gαi-dependent signaling through CXCR1 and CXCR2 was increased upon modification to [Cit5]CXCL8(1-77) or CXCL8(6-77). All CXCL8 variants promoted recruitment of β-arrestins 1 and 2 to CXCR1 and CXCR2. Compared to CXCL8(1-77), CXCL8(6-77) showed an enhanced potency to recruit β-arrestin 2 to both receptors, while for [Cit5]CXCL8(1-77) only the capacity to induce β-arrestin 2 recruitment to CXCR2 was increased. Both modifications had no biasing effect, i.e., did not alter the preference of CXCL8 to activate either Gαi-protein or β-arrestin-dependent signaling through its receptors. Our results support the concept that specific chemokine activities are fine-tuned by posttranslational modifications.
10
Burton, Victoria J., Alan M. Holmes, Loredana I. Ciuclan, Alexander Robinson, Jan S. Roger, Gabor Jarai, Andrew C. Pearce e David C. Budd. "Attenuation of leukocyte recruitment via CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II". Blood 118, n. 17 (27 ottobre 2011): 4750–58. http://dx.doi.org/10.1182/blood-2011-05-347393.
Abstract (sommario):
Abstract Previous studies from our group have demonstrated that bone morphogenetic protein receptor-II (BMPR-II), expressed on pulmonary artery endothelial cells, imparts profound anti-inflammatory effects by regulating the release of proinflammatory cytokines and promoting barrier function by suppressing the transmigration of leukocytes into the pulmonary vessel wall. Here we demonstrate that, in mice with endothelial-specific loss of BMPR-II expression (L1Cre(+);Bmpr2f/f), reduction in barrier function and the resultant pulmonary hypertension observed in vivo are the result of increased leukocyte recruitment through increased CXCR1/2 signaling. Loss of endothelial expressed BMPR-II leads to elevated plasma levels of a wide range of soluble mediators important in regulating leukocyte migration and extravasation, including the CXCR1/2 ligand, KC. Treatment of L1Cre(+);Bmpr2f/f mice with the CXCR1/2 antagonist SCH527123 inhibits leukocyte transmigration into lung and subsequently reverses the pulmonary hypertension. Our data have uncovered a previously unrecognized regulatory function of BMPR-II, which acts to regulate the expression of CXCR2 on endothelial cells, suggesting that increased CXCR2 signaling may also be a feature of the human pathology and that CXCR1/2 pathway antagonists may represent a novel therapeutic approach for treating pulmonary hypertension because of defects in BMPR-II expression.
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Browning, Darren D., Wade C. Diehl, Matthew H. Hsu, Ingrid U. Schraufstatter e Richard D. Ye. "Autocrine regulation of interleukin-8 production in human monocytes". American Journal of Physiology-Lung Cellular and Molecular Physiology 279, n. 6 (1 dicembre 2000): L1129—L1136. http://dx.doi.org/10.1152/ajplung.2000.279.6.l1129.
Abstract (sommario):
Interleukin (IL)-8 is a C-X-C chemokine that plays an important role in acute inflammation through its G protein-coupled receptors CXCR1 and CXCR2. In this study, we investigated the role of IL-8 as an autocrine regulator of IL-8 production and the signaling mechanisms involved in human peripheral blood mononuclear cells (MNCs). Sepharose-immobilized IL-8 stimulated a sevenfold increase in IL-8 production within 2 h. IL-8 induced the expression of its own message, and IL-8 biosynthesis was inhibited by cycloheximide and actinomycin D, indicating de novo RNA and protein synthesis. In contrast to MNCs, polymorphonuclear neutrophils did not respond to the immobilized IL-8 with IL-8 production despite cell surface expression of CXCR1 and CXCR2. Melanoma growth-stimulatory activity/growth-related protein-α (MGSA/GROα), which binds CXCR2 but not CXCR1, was unable to either stimulate IL-8 secretion in MNCs or desensitize these cells to respond to immobilized IL-8. The involvement of mitogen-activated protein kinase (MAPK) in IL-8-induced IL-8 biosynthesis was suggested by the ability of PD-98059, an inhibitor of MAPK kinase, to block this function. Furthermore, IL-8 induced a significant increase in extracellular signal-regulated kinase 2 phosphorylation, whereas MGSA/GROα was much less effective. These findings support the role of IL-8 as an autocrine regulator of IL-8 production and suggest that this function is mediated by CXCR1 through activation of MAPK.
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Inngjerdingen, Marit, Bassam Damaj e Azzam A. Maghazachi. "Expression and regulation of chemokine receptors in human natural killer cells". Blood 97, n. 2 (15 gennaio 2001): 367–75. http://dx.doi.org/10.1182/blood.v97.2.367.
Abstract (sommario):
Abstract Using flow cytometric and RNase protection assays, this study examined the expression of chemokine receptors in nonactivated natural killer (NK) cells and compared this expression with NK cells activated with interleukin (IL)-2, which either adhered to plastic flasks (AD) or did not adhere (NA). None of the NK cell subsets expressed CXCR2, CXCR5, or CCR5. The major differences between these cells include increased expression of CXCR1, CCR1, CCR2, CCR4, CCR8, and CX3CR1 in AD when compared to NA or nonactivated NK cells. The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-α, despite their lack of CXCR2 expression. Pretreatment of these cells with anti-CXCR2 did not inhibit the chemotactic response to GRO-α. In addition, nonactivated and NA cells responded to fractalkine, although they lack the expression of CX3CR1. This activity was not inhibited by anti-CX3CR1. Viral macrophage inflammatory protein (vMIP)-I, I-309, and TARC competed with the binding of 125I-309 to AD cells with varying affinities. Transforming growth factor (TGF)-β1 but not any other cytokine or chemokine examined including interferon (IFN)-γ, MIP-3β, macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) or I-309, up-regulated the expression of CXCR3 and CXCR4 on NK cell surface. This is correlated with increased chemotaxis of NK cells treated with TGF-β1 toward stromal cell–derived factor (SDF)-1α and interferon-inducible protein-10 (IP-10). Messenger RNA for lymphotactin, RANTES, MIP-1α, and MIP-1β, but not IP-10, monocyte chemotactic protein (MCP)-1, IL-8, or I-309 was expressed in all 3 NK cell subsets. Our results may have implications for the dissemination of NK cells at the sites of tumor growth or viral replication.
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de Jong, Madelon M. E., Cathelijne Fokkema, Natalie Papazian, Sabrin Tahri, Zoltan Kellermayer, Michael Vermeulen, Mark van Duin et al. "Inflammasome-Primed Myeloid Cells Maintain a Pro-Tumor Microenvironment in Multiple Myeloma". Blood 138, Supplement 1 (5 novembre 2021): 2679. http://dx.doi.org/10.1182/blood-2021-150327.
Abstract (sommario):
Abstract Background: Multiple myeloma (MM) disease progression is influenced by signals from the bone marrow (BM) microenvironment. Recently, we showed that the MM BM is characterized by inflammatory mesenchymal stromal cells (iMSCs) that transcribe MM survival factors and are predicted to recruit proliferating myeloma cells via CCL2-CCR2 interactions (de Jong et al. Nat Immunol. 2021). iMSCs also transcribed high levels of chemokines that can bind to CXCR1 and 2. Myeloid cells are known to express CXCR1/2, and have been implicated in both pro- and anti-tumor responses in various malignancies. Therefore, we hypothesized that iMSCs attract and influence myeloid populations in the MM BM. Results: Using flow cytometry, we verified expression of CXCR1/2 on myeloid cell populations in the BM of 5 newly diagnosed MM (NDMM) patients. CD15 + neutrophils were the most dominant population expressing these receptors, as 22.4% (± 9.8%) of cells expressed CXCR2 alone, and 72.6% (± 8.0%) expressed both CXCR1 and CXCR2. CD14 + monocytes only expressed CXCR2 (86.9% ± 15.8%). Importantly, less than 1% of myeloma cells expressed these receptors (n = 17 NDMM). As these findings suggested neutrophils and monocytes as potential targets of iMSC-mediated chemotaxis, we set out to identify MM-associated alterations in this population by performing single cell RNA sequencing of the full neutrophilic and monocytic lineages (n = 5 NDMM and 2 controls). In line with our flow cytometric data, CXCR1 transcripts were absent in monocytes, while CXCR2 was transcribed by classical monocytes of both myeloma patients and controls. Interestingly, CXCR1 and CXCR2 transcription was increased in mature neutrophils of MM patients compared to controls. Additionally, both mature classical monocytes as well as mature neutrophils of MM patients had an activated transcriptome as defined by increased transcription of C3AR1, SLPI, and IL6R, the plasma cell supportive factor TNFSF13B (encoding BAFF), and the inflammatory cytokines IL1B and IL18. Transcription of IL1B and IL18 can be regulated by pattern-recognition receptors (PRRs) binding damage-associated molecular patterns (DAMPs) resulting from e.g. matrix breakdown. Transcription of PRRs as TLR1, 2 and 4 was increased in mature neutrophils and classical monocytes of MM patients compared to controls. Secretion of IL-1β and IL-18 relies on the cleavage of pro-forms of these cytokines by the inflammasome, a multiprotein complex that is assembled in response to alarmins. Transcription of inflammasome components PYCARD, NLRP3 and CASP1 was increased in mature neutrophils and classical monocytes of patients with MM. Additionally, protein levels of both IL-18 and IL-1β are increased in BM plasma from MM patients, implicating activated neutrophils and monocytes as a potential sources of these cytokines. Conclusion: In MM, mature neutrophils and classical monocytes are activated and might interact with iMSCs via CXCR1 and/or 2. Moreover, these myeloid cells are inflammasome-primed and are likely to be sources of the increased IL-1β levels in the MM BM. Therefore, myeloid cells and iMSCs may form a feed-forward loop in which myeloid cells contribute to a pro-MM environment by maintaining iMSC and by directly providing BAFF to tumor cells. Disclosures Broyl: Celgene/BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Sonneveld: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.
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Troppan, Katharina, Kerstin Wenzl, Peter Neumeister, Christine Beham-Schmid, Martina Przekopowitz, Hildegard T. Greinix, Helmut Schaider e Alexander JA Deutsch. "The Chemokine Receptor Profile As Distinctive Criterion Between Normal B-Cell Subsets and As Potential Discriminative Marker to Identify the Cell of Origin in Patients with Chronic Lymphocytic Leukemia and Richter Syndrome". Blood 126, n. 23 (3 dicembre 2015): 3890. http://dx.doi.org/10.1182/blood.v126.23.3890.3890.
Abstract (sommario):
Abstract Chemokine receptors are G-protein-coupled cell surface receptors, which dissociate upon activation by their ligands and cause downstream signaling. Several studies have revealed the crucial contribution of chemokine receptors and their ligands in normal B-cell differentiation and development of hematopoietic malignancies. The Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Due to the lack of knowledge on the chemokine receptor, we aimed to investigate their expression profile in patients with CLL and Richter syndrome. Therefore, we investigated the mRNA expression levels of 18 known chemokine receptors (CCR1-CCR9, CXCR1-CXCR7, XCR1, CX3CR1) by using semi-quantitative real-time PCR on seven samples of paired (CLL and transformed DLBCL) RS samples, additionally four CLL samples -all of them subsequently transformed into DLBCL-, and eight transformed DLBCL samples originating from CLL. Additionally, 30 samples of de-novo DLBCL, including 10 germinal center B-cell (GCB) lymphomas, 12 non-germinal center B-cell lymphomas (non-GCB), and 8 unclassified DLBCL were included. Four samples of naïve B-cells (CD5 neg), CD5+ naïve B-cells and CD27+ memory B-cells (n=12) served as non-neoplastic controls. No differences in the chemokine receptor profile were detected between CD5+ and negative naïve B-cells. When comparing CD27+ memory B-cells to naïve B-cells a significant lower expression level was found for CCR7 (7-fold), CXCR4 (4-fold), and CXCR5 (1.5 fold). CCR7 (5-fold) and CXCR4 (5-fold) were also lower expressed in CD27+ memory B-cells compared to CD5+ naïve B-cells. Five out of 18 chemokine receptors were differentially expressed comparing the distinct normal B-cell subsets with RS samples. Comparing CLL samples and RS samples to CD5+ naïve B-cells, CXCR4 (12-fold for CLLs and 10-fold for RS samples) and CXCR5 (2-fold for CLLs and 2.4-fold for RS samples) were lower expressed, whereas CXCR3 (10-fold for CLLs and 8.5-fold for the transformed samples) was higher expressed and CCR5 de-novo expressed. Compared to naïve B-cells, the same chemokine receptors were deregulated: CXCR4 (10-fold for CLLs and 8.5-fold for the RS samples) and CXCR5 (2-fold for CLLs and 2.4-fold for the transformed samples) were lower expressed, CXCR3 (45-fold for CLLs and 30-fold for the transformed samples) was higher expressed and CCR5 was de-novo expressed. Comparing CLL samples and transformed RS samples to CD27+ memory B-cells, CCR5 (5.1-fold for CLLs and 4.3-fold for the RS samples) and CCR7 (8.7-fold for CLLs and 10-fold for the transformed samples) were higher expressed in both malignancies. Only one chemokine receptor was found to be differentially expressed in our seven paired RS samples: CCR6 showed a trend of a higher expression (1.4-fold) in CLL components. Considering RS and GCB DLBCL, CCR1, CCR5, and CXCR6 were found to be significantly down-regulated in RS (at least 4-fold), in contrast to CCR7 and CXCR4, which showed higher expression levels in RS (6-fold). CCR1 and CCR5 were lower expressed comparing RS and non-GCB DLBCL (25-fold and 8-fold), whereas CCR7 again, together with CXCR7, was higher expressed (3- fold and 6-fold respectively). Our data indicate a difference in the chemokine receptor profile within normal B-cell subsets. These differences are also reflected in the different expression profile of low and high aggressive component of CLL/RS compared to the distinct B cell subtypes. Hence, in future these multiple deregulated CC and CXC receptors might serve as a further hint in identifying the cell of origin of different B-cell malignancies. Disclosures No relevant conflicts of interest to declare.
15
Teijeira, Alvaro, Saray Garasa, Itziar Migueliz, Assunta Cirella e Ignacio Melero. "755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020): A803. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0755.
Abstract (sommario):
BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.
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Bie, Yaqin, Wei Ge, Zhibin Yang, Xianshuo Cheng, Zefeng Zhao, Shengjie Li, Wenchao Wang et al. "The Crucial Role of CXCL8 and Its Receptors in Colorectal Liver Metastasis". Disease Markers 2019 (20 novembre 2019): 1–12. http://dx.doi.org/10.1155/2019/8023460.
Abstract (sommario):
CXCL8 (also known as IL-8) can produce different biological effects by binding to its receptors: CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC). CXCL8 and its receptors are associated with the development of various tumor types, especially colorectal cancer and its liver metastases. In addition to promoting angiogenesis, proliferation, invasion, migration, and the survival of colorectal cancer (CRC) cells, CXCL8 and its receptors have also been known to induce the epithelial-mesenchymal transition (EMT) of CRC cells, to help them to escape host immunosurveillance as well as to enhance resistance to anoikis, which promotes the formation of circulating tumor cells (CTCs) and their colonization of distant organs. In this paper, we will review the established roles of CXCL8 signaling in CRC and discuss the possible strategies of targeting CXCL8 signaling for overcoming CRC drug resistance and cancer progression, including direct targeting of CXCL8/CXCR1/2 or indirect targeting through the inhibition of CXCL8-CXCR1/2 signaling.
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Ullman, Nicholas A., Luis I. Ruffolo, Katherine M. Jackson, Alexander Chacon, Mary Georger, Rachel Jewell, Brian A. Belt, Dean Maeda, John Zebala e David Linehan. "CXCR1/2 blockade to enhance response to immune checkpoint inhibition in an aggressive orthotopic pancreatic adenocarcinoma model." Journal of Clinical Oncology 38, n. 5_suppl (10 febbraio 2020): 19. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.19.
Abstract (sommario):
19 Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths, with the incidence expected to rise in the coming years. Despite conventional chemotherapy and advances in immune checkpoint blockade, 5 year survival remains a dismal 8%. Intratumoral accumulation of granulocytic myeloid derived suppressor cells (G-MDSC) pose a significant barrier to treatment as they contribute to immune evasion by PDAC and correlate with poor prognosis. The ELR+ CXC chemokine receptors CXCR1 and CXCR2 (CXCR1/2) contribute to peripheral neutrophil migration into tissues and have been implicated in tumor mediated G-MDSC recruitment to the tumor microenvironment. Here we present our findings using an orally dosed CXCR1/2 inhibitor, SX-682, in an orthotopic PDAC model. Methods: C57BL/6 mice underwent orthotopic injections with KP2 cells. Mice were randomized into five groups (Table) receiving three weeks of FOLFIRINOX with combinations of SX-682 and/or checkpoint inhibition (anti-PD1/anti-CTLA4). FOLFIRINOX was dosed weekly for three weeks. Checkpoint inhibition was administered twice weekly. Chow weights were monitored for consumption of SX-682. Results: The simultaneous administration of FOLFIRINOX with SX-682 combined with checkpoint inhibition (triple therapy) resulted in a significant increase in survival compared to other groups (p = 0.0001). Notably, there was a significant increase in survival with triple therapy versus FOLFIRINOX plus checkpoint alone (p = 0.0259). Median survival of the triple therapy group was 42.5 days, compared to 37 days with checkpoint inhibition (p = <0.05). There were no differences in chow consumption between the control and medicated chow groups. Conclusions: CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. [Table: see text]
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Molczyk, Caitlin, Elizabeth Thomas, Lubaba Zaman, Paran Goel e Rakesh K. Singh. "Abstract 894: CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 894. http://dx.doi.org/10.1158/1538-7445.am2022-894.
Abstract (sommario):
Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States. Often diagnosed late in disease progression, PDAC is notorious for chemotherapy resistance as well as having metastases. A cell population of interest aiding in this progression is the cancer stem cell (CSC). These cells are known for having high resistance to chemotherapy, along with propagating and re-building the tumor after most non-CSCs have been therapeutically targeted. Previous studies have determined CXCR4, ALDH1, CD24, CD44, and CD133 are markers of PDAC CSCs. In the present study, we investigated CXCR1 as a marker and therapeutic target for PDAC CSCs. CXCR1 is a G-coupled transmembrane protein receptor with downstream effects known to aid in anti-apoptosis, proliferation, and angiogenesis via binding CXCL8 and CXCL6. Already known to be a CSC marker and target in triple-negative breast cancer, initial studies by Chen et al. of CXCR1 in PDAC demonstrate CXCL8 induces increased tumorsphere formation in vitro, leading us to investigate CXCR1 in PDAC CSCs. Considering these findings, we hypothesized that PDAC cells with high CXCR1 activity exhibit increased CSC-like characteristics, and targeting CXCR1 will reduce those characteristics. To investigate the role of CXCR1 in PDAC CSC-like phenotype, we used two PDAC cell lines, CD18/HPAF and T3M4, and developed gemcitabine resistant (GemR) counterparts. These GemR cell lines were shown to have over 10-fold higher resistance than their respective parent cell lines. We treated with the CXCR1/2 antagonist navarixin at concentrations known to inhibit CXCR1. Using the parent cell lines’ relative IC50 concentrations for each drug, we treated cells for 72 hours. We used qRT-PCR and ELISAs for analysis of several known CSC markers and CXCR1 axis expression. From our results, we see the beginning trends of GemR cells having increased expression of CSC markers as well as gemcitabine-treated parent and resistant cells having increased expression. Using flow cytometry, we evaluated the CXCR1+ cell populations post-control and gemcitabine treatment. The population of CXCR1+ cells was higher in the gemcitabine-treated groups. Together, our observations suggest an association between CXCR1 and the CSC-like phenotype in PDAC. Citation Format: Caitlin Molczyk, Elizabeth Thomas, Lubaba Zaman, Paran Goel, Rakesh K. Singh. CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 894.
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Stadlbauer, V., R. P. Mookerjee, G. A. K. Wright, N. A. Davies, G. Jürgens, S. Hallström e R. Jalan. "Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis". American Journal of Physiology-Gastrointestinal and Liver Physiology 296, n. 1 (gennaio 2009): G15—G22. http://dx.doi.org/10.1152/ajpgi.90512.2008.
Abstract (sommario):
Neutrophil dysfunction in alcoholic hepatitis is associated with endotoxemia and an increased incidence of infection, but the mechanism is unclear. We aimed to investigate the role of Toll-like-receptors (TLR)2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Neutrophils from healthy volunteers were incubated with alcoholic hepatitis patients’ plasma ( n = 12) with and without TLR2, 4, or 9 antagonists and with and without human albumin. TLR2, 4, and 9 expression, neutrophil oxidative burst, phagocytosis, and CXCR1+2 expression were measured by FACS analysis. Patients’ plasma increased oxidative burst, decreased CXCR1+2 expression, and decreased phagocytosis of normal neutrophils in association with increased expression of TLR2, 4, and 9 and depletion of ATP. Inhibition of TLR2, 4, and 9 prevented the increase in oxidative burst and the decrease in CXCR1 and CXCR2 expression but did not prevent phagocytic dysfunction. Incubation with albumin completely prevented the patient plasma induced neutrophil dysfunction. Increased expression of TLR2, 4, and 9 is associated with neutrophil dysfunction, endotoxemia, and energy depletion. TLR2, 4, and 9 inhibition does not improve phagocytosis, indicating that TLR overexpression may be the result and not the cause of neutrophil activation. Albumin, an endotoxin scavenger, prevents the deleterious effect of patients’ plasma on neutrophil phagocytosis, resting burst, and TLR expression.
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Takata, Hiroshi, Takuya Naruto e Masafumi Takiguchi. "Functional heterogeneity of human effector CD8+ T cells". Blood 119, n. 6 (9 febbraio 2012): 1390–98. http://dx.doi.org/10.1182/blood-2011-03-343251.
Abstract (sommario):
AbstractEffector CD8+ T cells are believed to be terminally differentiated cells having cytotoxic activity and the ability to produce effector cytokines such as INF-γ and TNF-α. We investigated the difference between CXCR1+ and CXCR1− subsets of human effector CD27−CD28−CD8+ T cells. The subsets expressed cytolytic molecules similarly and exerted substantial cytolytic activity, whereas only the CXCR1− subset had IL-2 productivity and self-proliferative activity and was more resistant to cell death than the CXCR1+ subset. These differences were explained by the specific up-regulation of CAMK4, SPRY2, and IL-7R in the CXCR1− subset and that of pro-apoptotic death-associated protein kinase 1 (DAPK1) in the CXCR1+ subset. The IL-2 producers were more frequently found in the IL-7R+ subset of the CXCR1− effector CD8+ T cells than in the IL-7R− subset. IL-7/IL-7R signaling promoted cell survival only in the CXCR1− subset. The present study has highlighted a novel subset of effector CD8+ T cells producing IL-2 and suggests the importance of this subset in the homeostasis of effector CD8+ T cells.
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Мурашко, Д. И., А. Д. Таганович e Н. Н. Ковганко. "Combined Determination of CXCR1, CXCR2, Hyaluronic Acid and CYFRA 21-1 Receptors in the Blood in the Diagnosis of Non-Small Cell Lung Cancer". Евразийский онкологический журнал, n. 3 (1 novembre 2022): 201–16. http://dx.doi.org/10.34883/pi.2022.10.3.014.
Abstract (sommario):
Немелкоклеточный рак легкого (НМКРЛ) занимает большую часть в структуре заболеваемости раком легкого. НМКРЛ является неоднородным заболеванием и включает в себя 2 основных гистологических подтипа: аденокарциному (АК) и плоскоклеточный рак (ПКРЛ). В настоящее время не существует специфичных биомаркеров, позволяющих с достаточной точностью судить о распространенности опухоли при этом заболевании. Результаты проведенного исследования свидетельствуют, что плотность расположения (MFI) CXCR1 в гранулоцитах, доля лимфоцитов, снабженных CXCR2, уровень гиалуроновой кислоты (ГК) и CYFRA 21-1 в крови пациентов с АК и ПКРЛ существенно выше уже при I стадии, чем у здоровых людей, и демонстрируют дальнейший рост на последующих стадиях. Диагностические параметры определения их уровня в крови пациентов с АК и ПКРЛ были выше, чем при измерении«классического» опухолеассоциированного антигена CYFRA 21-1. В целях дальнейшего повышения диагностических параметров отдельных показателей был проведен многофакторный (регрессионный) анализ. В ходе анализа создано 6 регрессионных уравнений. Первое включает MFI CXCR1 в гранулоцитах и уровень ГК в крови и позволяет отличить пациентов с I и II стадиями АК от здоровых людей (эффективность – 92,4%). Второе включает MFI CXCR1 в гранулоцитах, долю лимфоцитов, снабженных CXCR2, и концентрацию CYFRA 21-1 в крови и позволяет отличить пациентов с I и II стадиями АК от III и IV ее стадий (эффективность – 92,0%). Третье уравнение включает MFI CXCR1 в гранулоцитах, долю лимфоцитов, снабженных CXCR2, и уровень ГК в крови и позволяет отличить I стадию АК от II (эффективность – 96,1%). Четвертое включает долю лимфоцитов, снабженных CXCR2, и уровень ГК в сыворотке крови для отличия пациентов с I и II стадиями ПКРЛ от здоровых людей (эффективность – 92,7%). Пятое включает долю лимфоцитов, снабженных CXCR2, и уровень ГК в крови и позволяет отличать пациентов с I и II стадиями от III и IV стадий ПКРЛ (эффективность – 90,4%). Шестое уравнение включает долю лимфоцитов, снабженных CXCR2, и уровень ГК в крови и может использоваться для отличия I от II стадии ПКРЛ c эффективностью 93,1%. Non-small cell lung cancer (NSCLC) occupies a large part in the structure of lung cancer incidence. NSCLC is a heterogeneous disease and includes two main histological subtypes: adenocarcinoma (AC) and squamous cell carcinoma (SCC). Currently, there are no specific biomarkers that allow one to judge with sufficient accuracy the extent of the tumor in this disease. The results of the study indicate that the location density (MFI) of CXCR1 in granulocytes, the proportion of lymphocytes supplied with CXCR2, the level of hyaluronic acid (HA) and CYFRA 21-1 in the blood of patients with AC and SCC are significantly higher than in healthy people, already at I stages of these diseases and show further growth in subsequent stages. Diagnostic parameters for determining their level in the blood of patients with AC and SCC were higher than when measuring the "classical" tumor-associated antigen CYFRA 21-1. In order to further improve the diagnostic parameters of individual indicators, a multivariate (regression) analysis was carried out. During the analysis, 6 regression equations were created. The first includes MFI CXCR1 in granulocytes and the level of HA in the blood and makes it possible to distinguish patients with stages I and II of AC from healthy people (efficiency – 92.4%). The second includes MFI CXCR1 in granulocytes, the proportion of lymphocytes equipped with CXCR2, and the concentration of CYFRA 21-1 in the blood and allows to distinguish patients with stages I and II of AC from stages III and IV (efficiency – 92.0%). The third equation includes MFI CXCR1 in granulocytes, the proportion of lymphocytes equipped with CXCR2, and the level of HA in the blood and allows you to distinguish stage I from AK II (efficiency – 96.1%). The fourth includes the proportion of lymphocytes carrying CXCR2 and the level of HA in the blood serum to distinguish patients with stages I and II SCC from healthy people (efficiency – 92.7%). The fifth includes the proportion of lymphocytes equipped with CXCR2 and the level of HA in the blood and allows you to distinguish patients with I and II from III and IV stages of SCC (efficiency – 90.4%). The sixth equation includes the proportion of lymphocytes carrying CXCR2 and the level of HA in the blood and can be used to distinguish stage I from stage II SCC with 93.1% efficiency.
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Petering, Holger, Otto Götze, Daniela Kimmig, Regina Smolarski, Alexander Kapp e Jörn Elsner. "The Biologic Role of Interleukin-8: Functional Analysis and Expression of CXCR1 and CXCR2 on Human Eosinophils". Blood 93, n. 2 (15 gennaio 1999): 694–702. http://dx.doi.org/10.1182/blood.v93.2.694.
Abstract (sommario):
Abstract Chemokines play an important role in attracting granulocytes into sites of inflammation. Two chemokine subfamilies differ in their biologic activity for different granulocyte subsets. Whereas CXC chemokines such as interleukin-8 (IL-8) activate predominantly neutrophils, CC chemokines such as RANTES and eotaxin activate predominantly eosinophils. However, controversial results have been published in the past regarding the biologic role of IL-8 in eosinophil activation, particularly in allergic diseases. In this study, we investigated the functional evidence and expression of both IL-8 receptors, CXCR1 and CXCR2, on highly purified human eosinophils. In the first set of experiments, a chemotaxis assay was performed showing that IL-8 did not induce chemotaxis of eosinophils. In addition, and in contrast to neutrophils and lymphocytes, IL-8 did not induce a rapid and transient release of cytosolic free Ca2+([Ca2+]i) in eosinophils, even after preincubation with TH1- and TH2-like cytokines. To investigate whether neutrophil contamination might be responsible for the reported IL-8 effects on eosinophils, neutrophils were added to highly purified eosinophils from the same donor in different concentrations. Interestingly, as little as 5% of neutrophil contamination was sufficient to induce an increase of [Ca2+]iafter stimulation with IL-8. Flow cytometry experiments with monoclonal antibodies against both IL-8 receptors demonstrated no expression of CXCR1 and CXCR2 on eosinophils before or after cytokine activation. Reverse transcriptase-polymerase chain reaction experiments showed that eosinophils, in contrast to neutrophils and lymphocytes, did not express mRNA for CXCR1 and CXCR2. In summary, this study clearly demonstrates that CXCR1 and CXCR2 are not expressed on human eosinophils, even after priming with different bioactive cytokines. Because the CXC chemokine IL-8 did not induce in vitro effects on human eosinophils, IL-8 may also not contribute in vivo to the influx of eosinophil granulocytes into sites of allergic inflammation. Our results suggest that CC chemokines such as eotaxin, eotaxin-2, and MCP-4 are predominant for the activation of eosinophils.
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Petering, Holger, Otto Götze, Daniela Kimmig, Regina Smolarski, Alexander Kapp e Jörn Elsner. "The Biologic Role of Interleukin-8: Functional Analysis and Expression of CXCR1 and CXCR2 on Human Eosinophils". Blood 93, n. 2 (15 gennaio 1999): 694–702. http://dx.doi.org/10.1182/blood.v93.2.694.402k31_694_702.
Abstract (sommario):
Chemokines play an important role in attracting granulocytes into sites of inflammation. Two chemokine subfamilies differ in their biologic activity for different granulocyte subsets. Whereas CXC chemokines such as interleukin-8 (IL-8) activate predominantly neutrophils, CC chemokines such as RANTES and eotaxin activate predominantly eosinophils. However, controversial results have been published in the past regarding the biologic role of IL-8 in eosinophil activation, particularly in allergic diseases. In this study, we investigated the functional evidence and expression of both IL-8 receptors, CXCR1 and CXCR2, on highly purified human eosinophils. In the first set of experiments, a chemotaxis assay was performed showing that IL-8 did not induce chemotaxis of eosinophils. In addition, and in contrast to neutrophils and lymphocytes, IL-8 did not induce a rapid and transient release of cytosolic free Ca2+([Ca2+]i) in eosinophils, even after preincubation with TH1- and TH2-like cytokines. To investigate whether neutrophil contamination might be responsible for the reported IL-8 effects on eosinophils, neutrophils were added to highly purified eosinophils from the same donor in different concentrations. Interestingly, as little as 5% of neutrophil contamination was sufficient to induce an increase of [Ca2+]iafter stimulation with IL-8. Flow cytometry experiments with monoclonal antibodies against both IL-8 receptors demonstrated no expression of CXCR1 and CXCR2 on eosinophils before or after cytokine activation. Reverse transcriptase-polymerase chain reaction experiments showed that eosinophils, in contrast to neutrophils and lymphocytes, did not express mRNA for CXCR1 and CXCR2. In summary, this study clearly demonstrates that CXCR1 and CXCR2 are not expressed on human eosinophils, even after priming with different bioactive cytokines. Because the CXC chemokine IL-8 did not induce in vitro effects on human eosinophils, IL-8 may also not contribute in vivo to the influx of eosinophil granulocytes into sites of allergic inflammation. Our results suggest that CC chemokines such as eotaxin, eotaxin-2, and MCP-4 are predominant for the activation of eosinophils.
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Le Naour, Augustin, Mélissa Prat, Benoît Thibault, Renaud Mével, Léa Lemaitre, Hélène Leray, Marie-Véronique Joubert et al. "Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors". Journal of Molecular Cell Biology 12, n. 3 (3 settembre 2019): 202–15. http://dx.doi.org/10.1093/jmcb/mjz090.
Abstract (sommario):
Abstract Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients’ blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.
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Таганович, А. Д., Н. Н. Ковганко, Г. Л. Гуревич, Г. К. Новская, О. А. Будник, О. В. Готько e В. И. Прохорова. "Verification of Blood Inflammatory Biomarkers Changes in the Diagnosis of Non-Small Cell Lung Cancer". Евразийский онкологический журнал 12, n. 1 (25 marzo 2024): 64–72. http://dx.doi.org/10.34883/pi.2024.12.1.024.
Abstract (sommario):
Введение. Молекулярные участники воспаления рассматриваются в качестве потенциальных маркеров злокачественных новообразований, в частности немелкоклеточного рака легкого (НМРЛ). Однако количественные их изменения у пациентов с НМРЛ могут быть вызваны сопутствующей патологией легких воспалительной природы и не отражать в полной мере связь с опухолью. Цель. Сравнить уровень показателей воспаления в крови при НМРЛ, хронической обструктивной болезни легких (ХОБЛ) и пневмонии. Материалы и методы. Материалом для исследования служила кровь 217 пациентов с НМРЛ при их поступлении для стационарного лечения, 12 пациентов с ХОБЛ в стадии обострения и 13 пациентов с внебольничной острой пневмонией при поступлении в стационар и при выписке. В контрольную группу вошли 65 условно здоровых людей без легочной патологии. Определялись концентрация CYFRA 21-1 иммуноферментным методом; относительное количество рецепторов CXCR1 и CXCR2 в лимфоцитах, CXCR2 в моноцитах, плотность расположения CXCR2 на лимфоцитах и CXCR1 на гранулоцитах проточной цитометрией, отношения С-реактивный белок (СРБ) / альбумин, лимфоциты/моноциты, эозинофильные лейкоциты / моноциты. Результаты. При поступлении в стационар в связи с обострением хронического воспаления у пациентов с ХОБЛ и острым воспалением легочной ткани – у пациентов с пневмонией – уровень CYFRA 21-1 не изменился по сравнению с контрольной группой. Медиана относительного количества CXCR1 в лимфоцитах при НМРЛ выросла в 2,9 раза, при ХОБЛ – в 3,1 раза, а при пневмонии – в 3,6 раза. Интенсивность флюоресценции CXCR2 в лимфоцитах – 17%, 20,5% и 60% соответственно, интенсивность флюоресценции CXCR1 в гранулоцитах – 1,9, 2 и 2,1 раза соответственно. Самое выраженное увеличение по сравнению с контролем было у отношения СРБ/альбумин: НМРЛ – в 6,2 раза, ХОБЛ – в 9,4 раза, пневмония – 10,3 раза, во всех случаях за счет роста СРБ – 4,2, 6,6, 8,1 раза соответственно. При выписке из стационара по окончании лечения, критерием для которой была ремиссия у пациентов с ХОБЛ или рентгенологическое подтверждение отсутствия воспаления легочной ткани при пневмонии, уровень всех определяемых показателей снизился до контрольного, а отношения лимфоциты/моноциты – вырос до контрольного. Полученные данные демонстрируют зависимость исследуемых параметров крови от воспалительного процесса в легочной ткани. При этом причина воспаления не имеет значения. Заключение. У пациентов с НМРЛ в условиях ремиссии хронического воспаления или отсутствия острого воспалительного процесса происходящие изменения показателей воспаления отражают развитие и (или) рецидивирование опухоли. Introduction. Molecular participants in inflammation are considered as potential markers of malignant neoplasms, in particular, non-small cell lung cancer (NSCLC). However, their quantitative changes in patients with NSCLC may be caused by concomitant inflammatory lung pathology and do not fully reflect the relationship with the tumor. Purpose. Сomparison of blood levels of inflammation indicators in NSCLC, congestive obstructive pulmonary disease (COPD) and pneumonia. Materials and methods. The material for the study was the blood of 217 patients with NSCLC upon admission into the hospital, 12 patients with COPD during exacerbation, and 13 patients with community-acquired acute pneumonia upon admission to the hospital and at discharge. The control group included 65 apparently healthy people without pulmonary pathology. The concentration of CYFRA 21-1 was determined by enzyme immunoassay; relative number of CXCR1 and CXCR2 receptors in lymphocytes, CXCR2 in monocytes, density of CXCR2 on lymphocytes and CXCR1 on granulocytes by flow cytometry, C-reactive protein (CRP)/albumin, lymphocytes/monocytes, eosinophilic leukocytes/monocytes ratios. Results. Upon admission to the hospital due to exacerbation of chronic inflammation in patients with COPD and acute inflammation of the lung tissue in patients with pneumonia, the level of CYFRA 21-1 did not change compared with the control group. The median relative amount of CXCR1 in lymphocytes increased by 2.9 times in NSCLC, 3.1 times in COPD, and 3.6 times in pneumonia. The fluorescence intensity of CXCR2 in lymphocytes is 17%, 20.5% and 60%, respectively, the fluorescence intensity of CXCR1 in granulocytes is 1.9, 2 and 2.1 times, respectively. The most pronounced increase in comparison with the control was in the CRP/albumin ratio: NSCLC – 6.2 times, COPD – 9.4 times, pneumonia – 10.3 times, in all cases due to the increase in CRP – 4.2, 6.6, 8.1 times, respectively. At discharge from the hospital at the end of treatment, the criterion for which was remission in patients with COPD or radiological confirmation of the absence of inflammation of the lung tissue in pneumonia, the level of all determined indicators decreased to the control level, and the ratio of lymphocytes/monocytes increased to the control one. The data obtained demonstrate the dependence of the studied blood parameters on the inflammatory process in the lung tissue. The cause of inflammation does not matter. Conclusion. In NSCLC patients in remission of chronic inflammation or in the absence of an acute inflammatory process, the ongoing changes in inflammation indicators reflect the development and (or) recurrence of the tumor.
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Cho, Hee Seong, Young In Choi, Seon Uk Park, Yi Seul Han, Jean Kwon e Sung Jun Jung. "Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2". International Journal of Molecular Sciences 24, n. 3 (17 gennaio 2023): 1855. http://dx.doi.org/10.3390/ijms24031855.
Abstract (sommario):
Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.
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Xing, Dongqi, J. Michael Wells, Samantha S. Giordano, Wenguang Feng, Amit Gaggar, Jie Yan, Fadi G. Hage, Li Li, Yiu-Fai Chen e Suzanne Oparil. "Induced pluripotent stem cell-derived endothelial cells attenuate lipopolysaccharide-induced acute lung injury". Journal of Applied Physiology 127, n. 2 (1 agosto 2019): 444–56. http://dx.doi.org/10.1152/japplphysiol.00587.2018.
Abstract (sommario):
The chemokine receptors CXCR1/2 and CCR2/5 play a critical role in neutrophil and monocyte recruitment to sites of injury and/or inflammation. Neutrophil-mediated inflammation and endothelial cell (EC) injury are unifying factors in the pathogenesis of the acute respiratory distress syndrome. This study tested the hypothesis that systemic administration of rat-induced pluripotent stem cell (iPS)-derived ECs (iPS-ECs) overexpressing CXCR1/2 or CCR2/5 attenuates lipopolysaccharide (LPS)-induced acute lung injury. Rat iPS-ECs were transduced with adenovirus containing cDNA of CXCR1/2 or CCR2/5. Ovariectomized Sprague-Dawley rats (10 wk old) received intraperitoneal injection of LPS and intravenous infusion of 1) saline vehicle, 2) AdNull-iPS-ECs (iPS-ECs transduced with empty adenoviral vector), 3) CXCR1/2-iPS-ECs (iPS-ECs overexpressing CXCR1/2), or 4) CCR2/5-iPS-ECs (iPS-ECs overexpressing CCR2/5) at 2 h post-LPS. Rats receiving intraperitoneal injection of saline served as sham controls. Later (4 h), proinflammatory cytokine/chemokine mRNA and protein levels were measured in total lung homogenates by real-time RT-PCR and Luminex multiplex assays, and neutrophil and macrophage infiltration in alveoli was measured by immunohistochemical staining. Pulmonary microvascular permeability was assessed by the Evans blue technique, and pulmonary edema was estimated by wet-to-dry lung weight ratios. Albumin levels and neutrophil counts were assessed in bronchoalveolar lavage fluid at 24 h post-LPS. Both CXCR1/2-iPS-ECs and CCR2/5-iPS-ECs significantly reduced LPS-induced proinflammatory mediator expression, neutrophil and macrophage infiltration, pulmonary edema, and vascular permeability compared with controls. These provocative findings provide strong evidence that targeted delivery of iPS-ECs overexpressing CXCR1/2 or CCR2/5 prevents LPS-induced acute lung injury. NEW & NOTEWORTHY We have developed a novel approach to address neutrophil-mediated inflammation and endothelial damage by targeted delivery of rat-induced pluripotent stem cell (iPS)-derived endothelial cell (ECs)overexpressing chemokine receptors CXCR1/2 and CCR2/5 in injured lung tissue in a model of acute lung injury. We have demonstrated that intravenously transfused CXCR1/2-iPS-ECs and CCR2/5-iPS-ECs are recruited to lipopolysaccharide-injured lungs and attenuate lipopolysaccharide-induced parenchymal lung injury responses, including inflammatory mediator expression, inflammatory cell infiltration, and vascular leakage compared with controls.
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Wolf, Marlene, Maria Belen Delgado, Simon A. Jones, Beatrice Dewald, Ian Clark-Lewis e Marco Baggiolini. "Granulocyte chemotactic protein 2 acts via both IL- 8 receptors, CXCR1 and CXCR2". European Journal of Immunology 28, n. 1 (gennaio 1998): 164–70. http://dx.doi.org/10.1002/(sici)1521-4141(199801)28:01<164::aid-immu164>3.0.co;2-s.
29
Liu, Qian, Anping Li, Yijun Tian, Jennifer D. Wu, Yu Liu, Tengfei Li, Yuan Chen, Xinwei Han e Kongming Wu. "The CXCL8-CXCR1/2 pathways in cancer". Cytokine & Growth Factor Reviews 31 (ottobre 2016): 61–71. http://dx.doi.org/10.1016/j.cytogfr.2016.08.002.
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Blaser, Bradley Wayne, Jessica Moore, Brian LI, Owen J. Tamplin, Vera Binder e Leonard I. Zon. "IL-8 and CXCR1 Remodel the Vascular Niche to Promote Hematopoietic Stem and Progenitor Cell Engraftment". Blood 126, n. 23 (3 dicembre 2015): 783. http://dx.doi.org/10.1182/blood.v126.23.783.783.
Abstract (sommario):
Abstract The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSC/HSPC) engraftment during development and in recipients of hematopoietic stem cell transplantation (HSCT). Factors secreted by the hematopoietic microenvironment that promote HSC/HSPC engraftment in the developing zebrafish may therefore be therapeutic targets for enhancing HSC engraftment in patients undergoing HSCT. We previously described a novel behavior we called endothelial cuddling in which sinuosoidal endothelial cells of the niche make intimate interactions with stem cells. To find candidate extracellular factors regulating this behavior, gene expression profiling was performed on sorted zebrafish endothelial cells. Gene set enrichment analysis showed that expression of chemokines and TNF family members was significantly enriched in all endothelial cells. The leading edge gene sets included 16 chemokines and chemokine receptors. Thirteen of these genes were used as candidates in a gain-of-function screen to test whether overexpression was sufficient to stimulate the hematopoietic niche in favor of HSC engraftment. High level, global gene expression was induced at 36 and 48 hours post fertilization (hpf) using a heat shock-inducible system. One gene, CXCR1, enhanced HSC/HSPC engraftment when globally overexpressed (p=0.03, N=63). CXCR1 is a specific receptor for the chemokine IL-8/CXCL8 in higher vertebrates. Zebrafish IL-8 was used in similar gain of function experiments and was also sufficient to enhance HSC/HSPC engraftment (p=0.003, N=41). CXCR2 is a promiscuous chemokine receptor for IL-8, Gro-α and Gro-β and did not enhance HSC/HSPC engraftment in this system. To further characterize the effects of CXCR1 on HSC engraftment, it was overexpressed in transgenic zebrafish carrying a stem-cell specific reporter gene, Runx1:mCherry. HSC engraftment in the CHT was enhanced when CXCR1 expression was induced beginning at 36 hpf (3.0 +/- 2.0 vs 7.4 +/- 2.6 HSC per CHT) or 48 hpf (4.3 +/- 1.1 vs 9.4 +/- 3.6 HSC per CHT). Inhibition of CXCR1 signaling from 48 to 72 hpf using the selective CXCR1/2 antagonist, SB225002, decreased HSC engraftment in Runx1:mCherry animals (1.2 +/- 0.39 vs 0.4 +/- 0.2 HSC per CHT, p=0.03). We next hypothesized that overexpression of CXCR1 might also have effects on the endothelial cell niche itself. Using FLK1(VEGFR2):mCherry reporter zebrafish and 3-dimensional reconstruction of the CHT, we found that global overexpression of CXCR1 increased the volume of the endothelial cell niche (2.0 +/- 0.09 x 106 vs 2.4 +/- 0.1 x 106 μm3, p=0.005) while treatment with SB225002 reduced its volume (6.3 +/- 0.3 x 105 vs 4.9 +/- 0.5 x 105 µm3, p=0.04). Finally, we asked if CHT remodeling would still be enhanced if CXCR1 were constitutively expressed only within the endothelial cell niche. FLK1:CXCR1; FLK1:mCherry double transgenic animals had significantly increased CHT volume when compared with FLK1:mCherry single transgenic animals (1.1 +/- 0.05 x 106 vs 1.3 +/- 0.06 x 106 um3, p=0.02). These findings suggest a model whereby HSC/HSPCs actively participate in the remodeling of the endothelial niche via CXCR1/IL-8 in order to promote their own engraftment. Further, they suggest that CXCR1/IL-8 is a potential therapeutic target for enhancing HSC/HSPC engraftment in patients undergoing HSCT. Disclosures Zon: FATE Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Scholar Rock: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder.
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Penco-Campillo, Manon, Clément Molina, Patricia Piris, Nouha Soufi, Manon Carré, Marina Pagnuzzi-Boncompagni, Vincent Picco et al. "Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas". Cells 11, n. 23 (5 dicembre 2022): 3933. http://dx.doi.org/10.3390/cells11233933.
Abstract (sommario):
Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients’ quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood–brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.
32
Lee, Kyung-Soon, Edelmar Navaluna, Nicole M. Marsh, Eric M. Janezic e Chris Hague. "Development of a Novel SNAP-Epitope Tag/Near-Infrared Imaging Assay to Quantify G Protein-Coupled Receptor Degradation in Human Cells". SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, n. 4 (5 gennaio 2021): 570–78. http://dx.doi.org/10.1177/2472555220979793.
Abstract (sommario):
We have developed a novel reporter assay that leverages SNAP-epitope tag/near-infrared (NIR) imaging technology to monitor G protein-coupled receptor (GPCR) degradation in human cell lines. N-terminal SNAP-tagged GPCRs were subcloned and expressed in human embryonic kidney (HEK) 293 cells and then subjected to 24 h of cycloheximide (CHX)-chase degradation assays to quantify receptor degradation half-lives ( t1/2) using LICOR NIR imaging–polyacrylamide gel electrophoresis (PAGE) analysis. Thus far, we have used this method to quantify t1/2 for all nine adrenergic (ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3), five somatostatin (SSTR1, SSTR2, SSTR3, SSTR4, SSTR5), four chemokine (CXCR1, CXCR2, CXCR3, CXCR5), and three 5-HT2 (5HT2A, 5HT2B, 5HT2C) receptor subtypes. SNAP-GPCR-CHX degradation t1/2 values ranged from 0.52 h (ADRA1D) to 5.5 h (SSTR3). On the contrary, both the SNAP-tag alone and SNAP-tagged and endogenous β-actin were resistant to degradation with CHX treatment. Treatment with the proteasome inhibitor bortezomib produced significant but variable increases in SNAP-GPCR protein expression levels, indicating that SNAP-GPCR degradation primarily occurs through the proteasome. Remarkably, endogenous β2-adrenergic receptor/ADRB2 dynamic mass redistribution functional responses to norepinephrine were significantly decreased following CHX treatment, with a time course equivalent to that observed with the SNAP-ADRB2 degradation assay. We subsequently adapted this assay into a 96-well glass-bottom plate format to facilitate high-throughput GPCR degradation screening. t1/2 values quantified for the α1-adrenergic receptor subtypes (ADRA1A, ADRA1B, ADR1D) using the 96-well-plate format correlated with t1/2 values quantified using NIR-PAGE imaging analysis. In summary, this novel assay permits precise quantitative analysis of GPCR degradation in human cells and can be readily adapted to quantify degradation for any membrane protein of interest.
33
Laura, Brandolini, Benedetti Elisabetta, Ruffini Pier Adelchi, Russo Roberto, Cristiano Loredana, Antonosante Andrea, d’Angelo Michele et al. "CXCR1/2 pathways in paclitaxel-induced neuropathic pain". Oncotarget 8, n. 14 (20 febbraio 2017): 23188–201. http://dx.doi.org/10.18632/oncotarget.15533.
34
Pawlick, Rena L., John Wink, Andrew R. Pepper, Antonio Bruni, Nasser Abualhassen, Yasmin Rafiei, Boris Gala-Lopez, Mariusz Bral e A. M. James Shapiro. "Reparixin, a CXCR1/2 inhibitor in islet allotransplantation". Islets 8, n. 5 (21 giugno 2016): 115–24. http://dx.doi.org/10.1080/19382014.2016.1199303.
35
Lima, Leonardo R. de, Heloisa M. F. Mendes, Frederico M. Soriani, Danielle G. de Souza, Geraldo Eleno S. Alves, Mauro M. Teixeira e Rafael R. Faleiros. "Histologic and inflammatory lamellar changes in horses with oligofructose-induced laminitis treated with a CXCR1/2 antagonist". Pesquisa Veterinária Brasileira 36, n. 1 (gennaio 2016): 13–18. http://dx.doi.org/10.1590/s0100-736x2016000100002.
Abstract (sommario):
Abstract: With the hypothesis that blocking chemokine signaling can ameliorate acute laminitis, the aim was to evaluate the therapeutic effect of intravenous DF1681B, a selective antagonist for CXCR1 and CXCR2 (chemokine receptors), in an oligofructose equine laminitis model. To twelve mixed breed clinically healthy hoses with no previous history of hoof-related lameness was administered oligofructose (10g/kg given by nasogastric tube) and divided into two groups: treated (intravenous DF1681B at 30mg/kg 6, 12, 18, and 24h after oligofructose) and non-treated groups. Laminar biopsies were performed before and 12, 36, and 72h after administering oligofructose. Samples were stained with periodic acid-Schiff (PAS) and scored from 0 to 6 according to epidermal cell and basal membrane changes. The IL-1β, IL-6, and CXCL1 RNA expressions were determined by RT-PCR. Parametric and non-parametric tests were used to compare times within each group (P<0.05). The PAS grades and IL-1β and IL-6 RNA expression increased in the non-treated group, but remained constant in the treated horses. In conclusion, DF1681B therapy reduced laminar inflammation and epidermal deterioration in treated horses. CXCR1/2 blockage should be considered therapeutically for equine acute laminitis.
36
Henrot, Pauline, Renaud Prevel, Patrick Berger e Isabelle Dupin. "Chemokines in COPD: From Implication to Therapeutic Use". International Journal of Molecular Sciences 20, n. 11 (6 giugno 2019): 2785. http://dx.doi.org/10.3390/ijms20112785.
Abstract (sommario):
Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chemokine receptors. Here, we provide an overview of the evidence regarding chemokines involvement in COPD, and we hypothesize that a dysregulation of this tightly regulated system is critical in COPD evolution, both at a stable state and during exacerbations. Targeting chemokines and chemokine receptors could be highly attractive as a mean to control both chronic inflammation and bronchial remodeling. We present a special focus on the CXCL8-CXCR1/2, CXCL9/10/11-CXCR3, CCL2-CCR2, and CXCL12-CXCR4 axes that seem particularly involved in the disease pathophysiology.
37
Ghasemzadeh, Mehran, Zane S. Kaplan, Imala Alwis, Simone M. Schoenwaelder, Katrina J. Ashworth, Erik Westein, Ehteramolsadat Hosseini et al. "The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi". Blood 121, n. 22 (30 maggio 2013): 4555–66. http://dx.doi.org/10.1182/blood-2012-09-459636.
38
Wong, Yin Ping, Noorhafizah Wagiman, Jonathan Wei De Tan, Barizah Syahirah Hanim, Muhammad Syamil Hilman Rashidan, Kai Mun Fong, Naufal Naqib Norhazli et al. "Loss of CXC-Chemokine Receptor 1 Expression in Chorioamnionitis Is Associated with Adverse Perinatal Outcomes". Diagnostics 12, n. 4 (1 aprile 2022): 882. http://dx.doi.org/10.3390/diagnostics12040882.
Abstract (sommario):
Background: Chorioamnionitis complicates about 1–5% of deliveries at term and causes about one-third of stillbirths. CXC-chemokine receptor 1 (CXCR1) binds IL-8 with high affinity and regulates neutrophil recruitment. We aimed to determine the immunoexpression of CXCR1 in placentas with chorioamnionitis, and its association with adverse perinatal outcomes. Methods: A total of 101 cases of chorioamnionitis and 32 cases of non-chorioamnionitis were recruited over a period of 2 years. CXCR1 immunohistochemistry was performed, and its immunoexpression in placentas was evaluated. The adverse perinatal outcomes included intrauterine death, poor APGAR score, early neonatal death, and respiratory complications. Results: Seventeen cases (17/101, 16.8%) with chorioamnionitis presented as preterm deliveries. Lung complications were more common in mothers who were >35 years (p = 0.003) and with a higher stage in the foetal inflammatory response (p = 0.03). Notably, 24 cases (23.8%) of histological chorioamnionitis were not detected clinically. Interestingly, the loss of CXCR1 immunoexpression in the umbilical cord endothelial cells (UCECs) was significantly associated with foetal death (p = 0.009). Conclusion: The loss of CXCR1 expression in UCECs was significantly associated with an increased risk of adverse perinatal outcomes and could be used as a biomarker to predict adverse perinatal outcomes in chorioamnionitis. Further study is warranted to study the pathophysiology involved in the failure of CXCR1 expression in these cells.
39
Mekhloufi, Abdelilah, Andrea Kosta, Helena Stabile, Rosa Molfetta, Alessandra Zingoni, Alessandra Soriani, Marco Cippitelli et al. "Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor". Cancers 12, n. 2 (13 febbraio 2020): 440. http://dx.doi.org/10.3390/cancers12020440.
Abstract (sommario):
Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells.
40
Lippert, Undine, Metin Artuc, Andreas Grützkau, Annelie Möller, Anna Kenderessy-Szabo, Dirk Schadendorf, Johannes Norgauer et al. "Expression and Functional Activity of the IL-8 Receptor Type CXCR1 and CXCR2 on Human Mast Cells". Journal of Immunology 161, n. 5 (1 settembre 1998): 2600–2608. http://dx.doi.org/10.4049/jimmunol.161.5.2600.
Abstract (sommario):
Abstract To further elucidate mechanisms involved in mast cell accumulation at sites of cutaneous inflammation, we have studied the ability of human leukemic mast cells (HMC-1 cells) to express functionally active IL-8 receptors. Expression of mRNA for both types of IL-8 receptors (CXCR1 and CXCR2) was demonstrated by PCR and of both proteins by flow cytometry. Binding and competition studies with 125I-labeled IL-8 and its homologue melanoma growth stimulating activity (125I-labeled MGSA) revealed two specific binding sites for IL-8, K1 = 1.1 × 1011 M−1 and K2 = 5 × 107 M−1; and for MGSA, K1 = 2.8 × 1010 M−1 and K2 = 5 × 107 M−1. This finding was supported by a dose-dependent rise of cytosolic free calcium concentration ([Ca2+]i) induced by both chemokines and to a lesser extent by the homologue neutrophil-activating peptide-2 (NAP-2). A significant migratory response of human leukemic mast cells (HMC-1) was observed with all three chemokines at a range from 10−8 M to 10−9 M. Moreover, the formation of cellular F-actin was induced in a rapid, dose-dependent fashion, with a maximally 1.7-fold increase at 10−7 M. Using postembedding immunoelectron microscopy, we could show the expression of CXCR1 on the cytoplasmatic membrane of isolated human skin mast cells whereas CXCR2 was located in mast cell-specific granules. These findings demonstrate for the first time the functional expression of both types of IL-8 receptors on human mast cells, suggesting a role for their ligands during mast cell activation and recruitment.
41
Castelli, Vanessa, Laura Brandolini, Michele d’Angelo, Cristina Giorgio, Margherita Alfonsetti, Pasquale Cocchiaro, Francesca Lombardi, Annamaria Cimini e Marcello Allegretti. "CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling". Cells 10, n. 9 (6 settembre 2021): 2324. http://dx.doi.org/10.3390/cells10092324.
Abstract (sommario):
Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines’ effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.
42
Citro, Antonio, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani et al. "CXCR1/2 inhibition enhances pancreatic islet survival after transplantation". Journal of Clinical Investigation 122, n. 10 (1 ottobre 2012): 3647–51. http://dx.doi.org/10.1172/jci63089.
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Lima, Leonardo R., Heloisa M. Falcão Mendes, Frederico M. Soriani, Geraldo Eleno S. Alves, Danielle G. de Souza, Mauro M. Teixeira e Rafael R. Faleiros. "Reparixin, an antagonist of CXCR1/2, in experimental laminitis". Journal of Equine Veterinary Science 33, n. 10 (ottobre 2013): 871–72. http://dx.doi.org/10.1016/j.jevs.2013.08.055.
44
Lu, Min, Lijuan Xia, Mohamed E. Salama e Ronald Hoffman. "Enriched Populations of Human Megakaryocytic Cells Affect the Behavior of Myelofibrosis CD34+ Cells As Well As Cells Belonging to the MF Supportive Microenvironment". Blood 132, Supplement 1 (29 novembre 2018): 3057. http://dx.doi.org/10.1182/blood-2018-99-117062.
Abstract (sommario):
Abstract Objective The marrows and spleens of myelofibrosis (MF) patients are characterized by megakaryocytic (MK) hyperplasia as well as microenvironment (MicroE) abnormalities including increased micro-vessel density, stromal cell (SC) hyperplasia and fibrosis. MF is accompanied by dysregulation of inflammatory cytokines (INF-CyKs) which alter the tissue specific MicroE niches in which MF HSC reside. We hypothesized that MF MKs play a critical role in MF pathobiology and examined their potential to affect MF and normal CD34+ cells as well as marrow and splenic endothelial cells (EC) and SCs. Methods & Results MF MKP/MKs elaborate specific INF-CyKs. CD34+ cells were cultured in serum free medium with stem cell factor and thrombopoietin (TPO) for 7 days, and then cultured with TPO alone for an additional 7 days to generate cell population enriched for MK progenitor cells (MKPs) (CD34+CD41+) and MKs (CD34-/CD41+) (MKP/MK: 22-61% in normal and 27.6-54% in MF). MF MKP/MKs as compared to normal MKPs (nMKP/MKs) contained increased transcripts for several INF-CyKs including: IL-8 (31 fold), TGF-β (8 fold) and VEGF (93 fold). The transcripts for the P53 antagonist MDM2 (112 fold) and the activity of the transcription factor NF-κB were also increased. Furthermore, media conditioned by MF MKP/MKs contained increased protein levels of IL-8, TGF-β and VEGF (5.8, 1.4 and 5.2 fold, respectively) as compared to nMKP/MKs. Using immunohistochemistry, we demonstrated that IL-8 protein was present in normal and MF splenic SCs and ECs, but was exclusively present in MF splenic MKs. Plasma IL-8 levels were significantly elevated in MF patient plasma (p=0.0008). These data indicate that MF MKP/MKs elaborate a series of INF-CyKs which promote the development of MF. IL-8 promotes MF CD34+ cells proliferation. CXCR1 and CXCR2 are two receptors that bind IL-8. Flow cytometric analyses showed that MF CD34+ cells expressed higher levels of CXCR1 and CXCR2 than normal CD34+ cells (3.3 and 3.1 fold, respectively). Addition of IL-8 increased MF CD34+ cell numbers by 2 fold and assayable CFU-GM by 40% (p=0.033), but this effect was eliminated by the addition of reparixin, a CXCR1/CXCR2 antagonist (p=0.0055). MF MKP/MKs can alter the HSC MicroE. Using IHC and flow cytometry we observed that CXCR1 and CXCR2 were also expressed by splenic SCs and ECs and marrow mesenchymal stem cells. When SCs and ECs were incubated with equal numbers of normal or MF MKP/MKs, higher levels of SCF and VEGF were elaborated by SCs but not ECs. This effect was more pronounced with MF MKP/MKs as compared to nMKP/MKs (p=0.02 for SCF and p=0.003 for VEGF). By contrast, higher levels of IL-8 were elaborated by both ECs and SCs following co-cultivation with MF MKP/MKs (p=0.047 and p=0.03). The addition of reparixin to these co-cultures decreased the levels of VEGF and IL-8 to baseline. Co-culturing MF CD34+ cells with either SCs or ECs significantly increased the numbers of CD34+ cells, an effect which could be blocked by the addition of reparixin. These data indicate that MF MKP/MKs provide inflammatory signals that alter the MF MicroE which supports MF CD34+ cells and that these signals can be disrupted by drugs blocking IL-8-CXCR1/2 interactions. MF MKP/MKs and CD34+ cells can be targeted with ruxolitinib, the nutlin-RG7112 and a BET inhibitor. Treatment of MF CD34+ cells with low doses of RG7112, ruxolitinib, or JQ1 alone or in combinations decreased MF but not normal hematopoietic colony formation. Treatment of MF MKP/MKs with each of these agents decreased phosphor-NF-kB p65 levels as demonstrated by western blot and decreased the elaboration of IL-8 by 20 to 60%. Conclusion These data indicate that MF MKPs are characterized by increased transcripts for MDM2 as well as NF-κB activity contributing / leading to the MK hyperplasia characteristic of MF and the elaboration of a group of lineage specific cytokines (TGF-β, IL-8, VEGF) that not only affect MF CD34+ cells but also cells belonging to the MicroE (ECs and SCs) (Figure 1). The MF promoting activities of MF MKP/MKs can be effectively targeted with ruxolitinib, RG7112, and BET inhibitors. Furthermore reparixin can be utilized to interrupt the interactions between IL-8 and CXCR1/2 expressing cells (CD34+ cells, ECs and SCs). These data provide the preclinical rationale for the evaluation of combinations of drugs which can dampen the cascade of events that result when MF MKP/MKs interact with CD34+ cells and MicroE cells. Disclosures Hoffman: Summer Road: Research Funding; Merus: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Formation Biologics: Research Funding.
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Armstrong, Chris, Jonathan Coulter, Pamela Maxwell, Silvia Berlingeri, Joe M. O'Sullivan, Kevin Prise e David J. Waugh. "Sensitivity of PTEN-deficient prostate carcinoma cells to ionizing radiation through inhibition of treatment-induced CXCL8 signaling." Journal of Clinical Oncology 31, n. 6_suppl (20 febbraio 2013): 154. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.154.
Abstract (sommario):
154 Background: We recently demonstrated that loss of PTEN in CaP cell lines increases expression of the pro-inflammatory chemokine CXCL8. Increased expression and signalling of this chemokine is detectable in PIN-foci and increases with disease progression. Our objective was to determine how induction of CXCL8 signalling affects the sensitivity of PTEN-deficient CaP cells to radiotherapy, a major treatment modality used in locally-confined CaP. Methods: Established cell-based models of CaP with differential expression of PTEN were subjected to ionizing radiation (IR) under normal or hypoxic culture conditions. Changes in chemokine expression in CaP cells were analyzed by real-time PCR, immunoblotting, and ELISA. siRNA- or shRNA-directed strategies were used to repress PTEN expression and/or attenuate autocrine CXCL8 signalling by down-regulating CXCR1 and CXCR2 gene expression.The effects of modulating chemokine signaling on cell viability following exposure to clinically-relevant doses of IR were assessed by colony formation assays, cell proliferation analysis, and analysis of apoptosis and/or cellular senescence. Results: Exposure to IR (3 Gy) in normoxic and hypoxic cells increased gene expression of CXCL8 and its receptors CXCR1 and CXCR2, a response potentiated in PTEN depleted cells. Loss of PTEN had different effects on the sensitivity of CaP cell lines; shRNA-mediated loss of PTEN conferred increased radioresistance in DU145 cells but increased the sensitivity of 22Rv1 cells to IR. However, despite these variable responses, siRNA-mediated repression of CXCR1/2 expression increased the sensitivity of all PTEN-depleted cell-based models to IR, under both normal and hypoxic conditions. Interestingly, inhibition of CXCL8 signalling reinforced IR-induced senescence in PTEN-depleted 22Rv1 cells (Tp53 WT) but increased apoptosis in PTEN-depleted DU145 cells (Tp53 mutant). Conclusions: Targeting IR-induced autocrine CXCL8 signalling is a novel therapeutic strategy to enhance the sensitivity of PTEN-deficient CaP cells to IR, taking on added significance in cells harbouring mutations or loss of Tp53 expression.
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Kaur, Manpreet, Ramneek, C. S. Mukhopadhyay e Jaspreet Singh Arora. "PCR-SSCP and Sequencing of CXCR1 (IL8RA) Gene in Indian Water Buffalo". International Journal of Applied Sciences and Biotechnology 4, n. 2 (27 giugno 2016): 228–32. http://dx.doi.org/10.3126/ijasbt.v4i2.15128.
Abstract (sommario):
Genetic markers associated with inflammatory responses could help in selecting the animals susceptible/tolerant to mastitis. The selective breeding assisted by these markers could help to reduce the huge economic losses that are posed by various forms of mastitis. Onepossible marker is CXCR1, a chemokine receptor that is required for neutrophil migration to infection site. Therefore the present study was planned to identify genetic polymorphism (if any)in CXCR1 gene and associate it with subclinical mastitis in Riverine buffalo of Northern India. For this,two hundred healthy lactating water buffalo were randomly chosenfrom the herds maintained by various farmers in Kapurthala District of Punjab, India.Blood and milk samples of selected buffaloes werecollected. Screening of the animals for sub clinical mastitis was done by SCC and CMT assays of milk samples.Genomic DNA was isolated from blood samples by phenol chloroform method. The DNA of good quality was used for further analysis. PCR-SSCP was used to explore the polymorphism in 311 bp fragment of partial exon2 of CXCR1 gene. The 311 bp fragment of CXCR1 gene was found to be monomorphic in all the DNA samples screened of Indian water buffalo.Int J Appl Sci Biotechnol, Vol 4(2): 228-232
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Ruffini, P. A., L. Brandolini, R. Russo, A. Cimini e M. Allegretti. "CXCR1/2 inhibition prevents paclitaxel- and oxaliplatin-induced peripheral neuropathy". European Journal of Cancer 69 (dicembre 2016): S115. http://dx.doi.org/10.1016/s0959-8049(16)32943-4.
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Carreira, E. U., V. Carregaro, M. M. Teixeira, A. Moriconi, A. Aramini, W. A. Verri, S. H. Ferreira, F. Q. Cunha e T. M. Cunha. "Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain". European Journal of Pain 17, n. 5 (7 novembre 2012): 654–63. http://dx.doi.org/10.1002/j.1532-2149.2012.00240.x.
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Huang, Yunjia, Jichen Yang, Yong Zhang, Shuhong Kuang, Zongshan Shen e Wei Qin. "Blocking CXCR1/2 attenuates experimental periodontitis by suppressing neutrophils recruitment". International Immunopharmacology 128 (febbraio 2024): 111465. http://dx.doi.org/10.1016/j.intimp.2023.111465.
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Florey, Oliver J., Michael Johns, Olubukola O. Esho, Justin C. Mason e Dorian O. Haskard. "Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2". Blood 109, n. 9 (23 gennaio 2007): 3881–89. http://dx.doi.org/10.1182/blood-2006-08-044669.
Abstract (sommario):
Abstract Antiendothelial cell antibodies (AECAs) are commonly detectable in diseases associated with vascular injury, including systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Wegener granulomatosis, Behçet syndrome, and transplant arteriosclerosis. Here, we explore the hypothesis that these antibodies might augment polymorphonuclear leukocyte (PMN) adhesion to endothelium in inflammation. Initially, we established that a mouse IgG mAb bound to endothelial cells (ECs) significantly increased PMN adhesion to cytokine-stimulated endothelium in an FcγRIIa-dependent manner. Neutralizing antibodies, and adenoviral transduction of resting ECs, demonstrated that the combination of E-selectin, CXCR1/2, and β2 integrins is both necessary and sufficient for this process. We observed an identical mechanism using AECA IgG isolated directly from patients with SLE. Assembled immune complexes also enhanced PMN adhesion to endothelium, but, in contrast to adhesion because of AECAs, this process did not require CXCR1/2, was not inhibited by pertussis toxin, and was FcγRIIIb rather than FcγRIIa dependent. These data are the first to demonstrate separate nonredundant FcγRIIa and FcγRIIIb-mediated mechanisms by which EC-bound monomeric IgG and assembled immune complexes amplify leukocyte adhesion under dynamic conditions. Furthermore, the observation that FcγRIIa and CXCR1/2 cooperate to enhance PMN recruitment in the presence of AECAs suggests a mechanism whereby AECAs may augment tissue injury during inflammatory responses.