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1
Korbecki, Jan, Klaudyna Kojder, Patrycja Kapczuk, Patrycja Kupnicka, Barbara Gawrońska-Szklarz, Izabela Gutowska, Dariusz Chlubek, and Irena Baranowska-Bosiacka. "The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature." International Journal of Molecular Sciences 22, no. 2 (January 15, 2021): 843. http://dx.doi.org/10.3390/ijms22020843.
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Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors—CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.
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Tian, He, Liyu Wang, Yu Liu, Yalong Wang, Yujia Zheng, Tao Fan, Bo Zheng, et al. "Bioinformatics Analyses Reveals a Comprehensive Landscape of CXC Chemokine Family Functions in Non-Small Cell Lung Cancer." BioMed Research International 2021 (January 25, 2021): 1–34. http://dx.doi.org/10.1155/2021/6686158.
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Backgrounds. Lung cancer is a major source of tumor-related death each year with non-small cell lung cancer (NSCLC) being a prevalent subtype. The metastasis from NSCLC to the brain usually imposes many neuron disorders. Previous studies have suggested that communications among cancer cells and interstitial cells are essential in tumorigenesis and are influenced by chemokines. In the tumor microenvironment, CXC chemokines can participate in the shifting of immune cells and manage tumor cell condition, thus affecting the progression of cancer and patient destinies. However, the expression and values of CXC chemokine family in NSCLC have not been systematically illustrated using public databases. Methods. UALCAN, STRING, ONCOMINE, GeneMANIA, cBioPortal, GEPIA, TISIDB, TRRUST, TIMER, Kaplan-Meier Plotter, and R software were utilized in this study. Results. Based on the TIMER and UACLCAN databases, in LUAD patients, the expression levels of CXCL10, CXCL13, and CXCL14 were significantly elevated while the transcriptional levels of CXCL2/3/4/7/12/16 were significantly reduced; in LUSC patients, the expression levels of CXCL6/10/13/14 were significantly elevated while the expression levels of CXCL2/3/4/5/7/11/12/16/17 were significantly reduced. We found remarkable relevance between the pathological stages of LUAD patients and the expressions of CXCL8 (positive) and CXCL17 (negative). Similarly, there are significant correlations between the pathological stages of LUSC patients and the expressions of CXCL1/2/6/17. In LUAD, patients with low expression levels of CXCL1/4/7/8 and patients with high expression levels of CXCL12/14/16 were associated with a significantly better prognosis. But in LUSC, all correlations between chemokines and prognosis are statistically insignificant. Pairwise expression correlation analysis among CXC chemokines shows that there are 7 significant correlations (between CXCL1 and CXCL2, between CXCL1 and CXCL3, between CXCL1 and CXCL8, between CXCL2 and CXCL3, between CXCL4 and CXCL7, between CXCL9 and CXCL10, and between CXCL9 and CXCL11) in LUAD and 4 significant correlations (between CXCL1 and CXCL8, between CXCL2 and CXCL3, between CXCL4 and CXCL7, and between CXCL10 and CXCL11) in LUSC. Significant correlations between the expressions of CXC chemokines and the infiltration of six common types of immune cells were also discovered in both LUAD and LUSC. Conclusions. We provided a comprehensive landscape of the CXC chemokine family in LUAD and LUSC using the bioinformatics method and found differences between LUSC and LUAD in the field of CXC chemokines. Our study may help validate and identify known novel immunotherapeutic targets and prognostic biomarkers.
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Korbecki, Jan, Mateusz Bosiacki, Dariusz Chlubek, and Irena Baranowska-Bosiacka. "Bioinformatic Analysis of the CXCR2 Ligands in Cancer Processes." International Journal of Molecular Sciences 24, no. 17 (August 27, 2023): 13287. http://dx.doi.org/10.3390/ijms241713287.
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Human CXCR2 has seven ligands, i.e., CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8/IL-8—chemokines with nearly identical properties. However, no available study has compared the contribution of all CXCR2 ligands to cancer progression. That is why, in this study, we conducted a bioinformatic analysis using the GEPIA, UALCAN, and TIMER2.0 databases to investigate the role of CXCR2 ligands in 31 different types of cancer, including glioblastoma, melanoma, and colon, esophageal, gastric, kidney, liver, lung, ovarian, pancreatic, and prostate cancer. We focused on the differences in the regulation of expression (using the Tfsitescan and miRDB databases) and analyzed mutation types in CXCR2 ligand genes in cancers (using the cBioPortal). The data showed that the effect of CXCR2 ligands on prognosis depends on the type of cancer. CXCR2 ligands were associated with EMT, angiogenesis, recruiting neutrophils to the tumor microenvironment, and the count of M1 macrophages. The regulation of the expression of each CXCR2 ligand was different and, thus, each analyzed chemokine may have a different function in cancer processes. Our findings suggest that each type of cancer has a unique pattern of CXCR2 ligand involvement in cancer progression, with each ligand having a unique regulation of expression.
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YAMAMOTO, YURIE, KENJI KURODA, TOMOHIRO SERA, ATSUSHI SUGIMOTO, SHUHEI KUSHIYAMA, SADAAKI NISHIMURA, SHINGO TOGANO, et al. "The Clinicopathological Significance of the CXCR2 Ligands, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8 in Gastric Cancer." Anticancer Research 39, no. 12 (December 2019): 6645–52. http://dx.doi.org/10.21873/anticanres.13879.
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Mei, Junjie, M. Anna Kowalska, Ning Dai, Yuhong Liu, Kristin Hudock, Samthamby Jeyaseelan, Janet Lee, Susan Guttentag, Mortimer Poncz, and G. Scott Worthen. "Platelet CXCL7 and CXCL4 inhibit chemokine scavenging and improve innate immunity to bacterial infection (P1317)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 63.14. http://dx.doi.org/10.4049/jimmunol.190.supp.63.14.
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Abstract We recently demonstrated the critical role of CXCL5 in chemokine scavenging, neutrophil homeostasis and host defense to bacterial pneumonia. Here we generated Cxcl7-/- mice and found that Cxcl7 deletion also disrupted expression of CXCL4 and CXCL5, but did not affect expression of two other neutrophil chemokines, CXCL1 and CXCL2. Cxcl4, 7, 5 form a conserved genomic locus (14.5 kb in length) in both human and mice, suggesting their importance during evolution. Heparin treatment of blood led to over 10-fold more plasma CXCL4, but comparable plasma CXCL7 as compared to PBS treatment. In addition, the inactive PPBP form of murine CXCL7 showed considerable binding affinity with red cell DARC. We further delineated the role of CXCL7 and CXCL4 by comparing the phenotypes of Cxcl7-/- and Cxcl5-/- mice. CXCL7 and CXCL4 inhibit chemokine scavenging not only in blood, but also in tissues, and platelet-derived CXCL7 is present in alveolar space and peritoneum. In CXCL1- and nebulized LPS-induced acute lung inflammation models, K. pneumoniae pneumonia and bacteremia models, as compared to Cxcl5-/- mice, Cxcl7-/- mice showed attenuated neutrophil chemokine levels in tissues and blood, decreased neutrophil influx to the lung, and impaired innate immunity. This study is the first to reveal the central role of homeostatic CXCL7 and CXCL4 in increasing chemokine levels in blood and tissues, and potentiating neutrophil transmigration during inflammation and infection.
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Hong, Jung-Hee, and Young-Cheol Lee. "Anti-Inflammatory Effects of Cicadidae Periostracum Extract and Oleic Acid through Inhibiting Inflammatory Chemokines Using PCR Arrays in LPS-Induced Lung inflammation In Vitro." Life 12, no. 6 (June 8, 2022): 857. http://dx.doi.org/10.3390/life12060857.
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In this study, we aimed to evaluate the anti-inflammatory effects and mechanisms of CP and OA treatments in LPS-stimulated lung epithelial cells on overall chemokines and their receptors using PCR arrays. In addition, we aimed to confirm those effects and mechanisms in LPS-stimulated lung macrophages on some chemokines and cytokines. In our study, CP treatments significantly inhibited the inflammatory mediators CCL2, CCL3, CCL4, CCL5, CCL6, CCL9, CCL11, CCL17, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, CXCL7, CXCL10, TNF-α, and IL-6, while markedly suppressing NF-κB p65 nuclear translocation and the phosphorylations of PI3K p55, Akt, Erk1/2, p38, and NF-κB p65 in LPS-stimulated lung epithelial cells. CP treatments also significantly decreased the inflammatory mediators CCL2, CCL5, CCL17, CXCL1, and CXCL2, while markedly inhibiting phospho-PI3K p55 and iNOS expression in LPS-stimulated lung macrophages. Likewise, OA treatments significantly suppressed the inflammatory mediators CCL2, CCL3, CCL4, CCL5, CCL8, CCL11, CXCL1, CXCL3, CXCL5, CXCL7, CXCL10, CCRL2, TNF-α, and IL-6, while markedly reducing the phosphorylations of PI3K p85, PI3K p55, p38, JNK, and NF-κB p65 in LPS-stimulated lung epithelial cells. Finally, OA treatments significantly inhibited the inflammatory mediators CCL2, CCL5, CCL17, CXCL1, CXCL2, TNF-α, and IL-6, while markedly suppressing phospho-PI3K p55, iNOS, and Cox-2 in LPS-stimulated lung macrophages. These results prove that CP and OA treatments have anti-inflammatory effects on the inflammatory chemokines and cytokines by inhibiting pro-inflammatory mediators, including PI3K, Akt, MAPKs, NF-κB, iNOS, and Cox-2. These findings suggest that CP and OA are potential chemokine-based therapeutic substances for treating the lung and airway inflammation seen in allergic disorders.
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Hu, Jing, Qian Ji, Fei Chen, Xiaoqin Gong, Chuansheng Chen, Kaijun Zhang, Ye Hua, et al. "CXCR2 Is Essential for Radiation-Induced Intestinal Injury by Initiating Neutrophil Infiltration." Journal of Immunology Research 2022 (July 16, 2022): 1–9. http://dx.doi.org/10.1155/2022/7966089.
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Neutrophils, known as an important part of the immune system, are the most abundant leukocyte population in peripheral blood, but excessive recruitment will lead to tissue/organ injury. RNA sequencing showed that ionizing radiation significantly increased the expression of characteristic genes of neutrophils in intestinal tissues compared with liver and lung tissues. By clearing neutrophils with an anti-Ly6G antibody, we found that neutrophil infiltration is critical for irradiation-induced intestinal injury. CXCR2 is a G-protein-coupled receptor that mediates the migration of neutrophils by combining with its ligands. Compared with observations in liver and lung tissues, we found that CXCR2 and its ligands, including CXCL1, CXCL2, CXCL3, and CXCL5, were all significantly upregulated in irradiated intestinal tissues. Further studies showed that SB225002, an inhibitor of CXCR2, could effectively inhibit the chemotaxis of neutrophils and tissue damage mediated by the CXCL-CXCR2 signalling pathway.
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Situ, Yongli, Xiaoyong Lu, Yongshi Cui, Qinying Xu, Li Deng, Hao Lin, Zheng Shao, and Jv Chen. "Systematic Analysis of CXC Chemokine–Vascular Endothelial Growth Factor A Network in Colonic Adenocarcinoma from the Perspective of Angiogenesis." BioMed Research International 2022 (October 4, 2022): 1–19. http://dx.doi.org/10.1155/2022/5137301.
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Background. Tumor angiogenesis plays a vital role in tumorigenesis, proliferation, and metastasis. Recently, vascular endothelial growth factor A (VEGFA) and CXC chemokines have been shown to play vital roles in angiogenesis. Exploring the expression level, gene regulatory network, prognostic value, and target prediction of the CXC chemokine-VEGFA network in colon adenocarcinoma (COAD) is crucial from the perspective of tumor angiogenesis. Methods. In this study, we analyzed gene expression and regulation, prognostic value, target prediction, and immune infiltrates related to the CXC chemokine-VEGFA network in patients with COAD using multiple databases (cBioPortal, UALCAN, Human Protein Atlas, GeneMANIA, GEPIA, TIMER (version 2.0), TRRUST (version 2), LinkedOmics, and Metascape). Results. Our results showed that CXCL1/2/3/5/6/8/11/16/17 and VEGFA were markedly overexpressed, while CXCL12/13/14 were underexpressed in patients with COAD. Moreover, genetic alterations in the CXC chemokine-VEGFA network found at varying rates in patients with COAD were as follows: CXCL1/2/17 (2.1%), CXCL3/16 (2.6%), CXCL5/14 (2.4%), CXCL6 (3%), CXCL8 (0.8%), CXCL11/13 (1.9%), CXCL12 (0.6%), and VEGFA (1.3%). Promoter methylation of CXCL1/2/3/11/13/17 was considerably lower in patients with COAD, whereas methylation of CXCL5/6/12/14 and VEGFA was considerably higher. Furthermore, CXCL9/10/11 and VEGFA expression was notably correlated with the pathological stages of COAD. In addition, patients with COAD with high CXCL8/11/14 or low VEGFA expression levels survived longer than patients with dissimilar expression levels. CXC chemokines and VEGFA form a complex regulatory network through coexpression, colocalization, and genetic interactions. Moreover, many transcription factor targets of the CXC chemokine-VEGFA network in patients with COAD were identified: RELA, NFKB1, ZFP36, XBP1, HDAC2, SP1, ATF4, EP300, BRCA1, ESR1, HIF1A, EGR1, STAT3, and JUN. We further identified the top three miRNAs involved in regulating each CXC chemokine within the network: miR-518C, miR-369-3P, and miR-448 regulated CXCL1; miR-518C, miR-218, and miR-493 regulated CXCL2; miR-448, miR-369-3P, and miR-221 regulated CXCL3; miR-423 regulated CXCL13; miR-378, miR-381, and miR-210 regulated CXCL14; miR-369-3P, miR-382, and miR-208 regulated CXCL17; miR-486 and miR-199A regulated VEGFA. Furthermore, the CXC chemokine-VEGFA network in patients with COAD was notably associated with immune infiltration. Conclusions. This study revealed that the CXC chemokine-VEGFA network might act as a prognostic biomarker for patients with COAD. Moreover, our study provides new therapeutic targets for COAD, serving as a reference for further research in the future.
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Mu, Li, Shun Hu, Guoping Li, Ping Wu, Caihong Ren, Taiyu Lin, and Sheng Zhang. "Characterization of the Prognostic Values of CXCL Family in Epstein–Barr Virus Associated Gastric Cancer." Oxidative Medicine and Cellular Longevity 2022 (June 1, 2022): 1–24. http://dx.doi.org/10.1155/2022/2218140.
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Background. CXCL family is a class of secreted growth factors signaling through G-protein-coupled receptors, and abnormal expression is associated with the growth and progression of many tumors. However, their prognostic value has been poorly studied in Epstein–Barr virus- (EBV-) associated gastric cancer (EBVaGC). Therefore, it is of great significance to explore the prognostic value of the CXCL family in EBVaGC. Methods. CXCL family mRNA expression was analyzed in STAD data from The Cancer Genome Atlas (TCGA). Kaplan-Meier Plotter was used to assess the prognostic value of the CXCL family. Transcription factors (TFs) and miRNAs associated with the CXCL family were identified by TFCheckpoint, miRWalk, and ViRBase databases. The prognostic model was evaluated using the EBVaGC patient cohort GSE51575. Results. The mRNA expression of CXCL1/3/5/6/8/9/10/11/16 was significantly upregulated, while the expression of CXCL12/14 was downregulated in EBVaGC compared with normal tissues from TCGA-STAD. The mRNA expressions of CXCL9, CXCL10, CXCL11, and CXCL17 in EBVaGCs were higher than those in EBVnGCs, but the mRNA expressions of CXCL6, CXCL12, and CXCL17 were lower than those in EBVnGCs. The mRNA expression levels of CXCL9, CXCL10, and CXCL11 in EBVaGCs were higher than those in EBVnGCs regardless of the tumor stage. High mRNA expression of CXCL8 was associated with better OS in patients with EBVaGC, while high expression of CXCL9 was associated with better OS in patients with EBVnGC. We obtained 10 candidate potential transcription factors (TFs) associated with CXCLs: OTOP3, NKX6-2, NKX2-2, FEV, SMYD1, TRIMSO, TBX10, CDX1, SLC26A3, and ARC. 576 miRNA-mRNA interactions were obtained. Among them, 65 miRNAs were predicted to be correlated with CXCL6, CXCL9, CXCL10, and CXCL11. Similar to the results of TCGA-STAD, the GSE51575 dataset also showed that the mRNA expression levels of CXCL1/3/9/10/11/16 were markedly enhanced in EBVaGC tissues compared with corresponding normal gastric mucosa tissues, while the mRNA expression levels of CXCL12/14 were significantly reduced. The mRNA expression levels of CXCL3/9/10/11/13/17 were increased in EBVaGC compared with EBVnGC tissues. Conclusions. The expression differences of CXCL family members are closely associated with the progression of EBVaGC. Expression of CXCL9/10/11/17 mRNA may be a promising prognostic indicator for EBVaGC patients.
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Sun, Xiaoqi, Qunxi Chen, Lihong Zhang, Jiewei Chen, and Xinke Zhang. "Exploration of prognostic biomarkers and therapeutic targets in the microenvironment of bladder cancer based on CXC chemokines." Mathematical Biosciences and Engineering 18, no. 5 (2021): 6262–87. http://dx.doi.org/10.3934/mbe.2021313.
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<abstract> <sec><title>Background</title><p>Bladder cancer (BLCA) has a high rate of morbidity and mortality, and is considered as one of the most malignant tumors of the urinary system. Tumor cells interact with surrounding interstitial cells, playing a key role in carcinogenesis and progression, which is partly mediated by chemokines. CXC chemokines exert anti-tumor biological roles in the tumor microenvironment and affect patient prognosis. Nevertheless, their expression and prognostic values patients with BLCA remain unclear.</p> </sec> <sec><title>Methods</title><p>We used online tools, including Oncomine, UALCAN, GEPIA, GEO databases, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRUST (version 2.0), LinkedOmics, TCGA, and TIMER2.0 to perform the relevant analysis.</p> </sec> <sec><title>Results</title><p>The mRNA levels of C-X-C motif chemokine ligand (<italic>CXCL)1</italic>, <italic>CXCL5</italic>, <italic>CXCL6</italic>, <italic>CXCL7</italic>, <italic>CXCL9</italic>, <italic>CXCL10</italic>, <italic>CXCL11</italic>, <italic>CXCL13</italic>, <italic>CXCL16</italic>, and <italic>CXCL17</italic> were increased significantly increased, and those of <italic>CXCL</italic>2, <italic>CXCL3</italic>, and <italic>CXCL12</italic> were decreased significantly in BLCA tissues as assessed using the Oncomine, TCGA, and GEO databases. GEO showed that high levels of <italic>CXCL1</italic>, <italic>CXCL6</italic>, <italic>CXCL10</italic>, <italic>CXCL1</italic>1, and <italic>CXCL13</italic> mRNA expression are associated significantly with the poor overall survival (all p < 0.05), and similarly, those of <italic>CXCL2</italic> and <italic>CXCL12</italic> in the TCGA database (p < 0.05). The predominant signaling pathways involving the differentially expressed CXC chemokines are cell cycle, chemokine, and cytokine-cytokine receptor interaction. Moreover, transcription factors such as Sp1 transcription factor (SP1), nuclear factor kappa B subunit 1 (NFKB1), and RELA proto-oncogene, NF-KB subunit (RELA) were likely play critical roles in regulating CXC chemokine expression. LYN proto-oncogene, src family tyrosine kinase (LYN) and LCK proto-oncogene, src family tyrosine kinase (LCK) were identified as the key targets of these CXC chemokines. MicroRNAs miR200 and miR30 were identified as the main microRNAs that interact with several CXC chemokines through an miRNA-target network. The expression of these chemokines is closely associated with the infiltration of six categories of immune cells.</p> </sec> <sec><title>Conclusion</title><p>We explored the CXC chemokines superfamily-based biomarkers associated with BLCA prognosis using public databases, and provided possible chemokine targets for patients with BLCA.</p> </sec> </abstract>
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Roh, Yoon Seok, Bi Zhang, Rohit Loomba, and Ekihiro Seki. "TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 1 (July 1, 2015): G30—G41. http://dx.doi.org/10.1152/ajpgi.00031.2015.
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Although previous studies reported the involvement of the TLR4-TRIF pathway in alcohol-induced liver injury, the role of TLR2 and TLR9 signaling in alcohol-mediated neutrophil infiltration and liver injury has not been elucidated. Since alcohol binge drinking is recognized to induce more severe form of alcohol liver disease, we used a chronic-binge ethanol-feeding model as a mouse model for early stage of alcoholic hepatitis. Whereas a chronic-binge ethanol feeding induced alcohol-mediated liver injury in wild-type mice, TLR2- and TLR9-deficient mice showed reduced liver injury. Induction of neutrophil-recruiting chemokines, including Cxcl1, Cxcl2, and Cxcl5, and hepatic neutrophil infiltration were increased in wild-type mice, but not in TLR2- and TLR9-deficient mice. In vivo depletion of Kupffer cells (KCs) by liposomal clodronate reduced liver injury and the expression of Il1b, but not Cxcl1, Cxcl2, and Cxcl5, suggesting that KCs are partly associated with liver injury, but not neutrophil recruitment, in a chronic-binge ethanol-feeding model. Notably, hepatocytes and hepatic stellate cells (HSCs) produce high amounts of CXCL1 in ethanol-treated mice. The treatment with TLR2 and TLR9 ligands synergistically upregulated CXCL1 expression in hepatocytes. Moreover, the inhibitors for CXCR2, a receptor for CXCL1, and MyD88 suppressed neutrophil infiltration and liver injury induced by chronic-binge ethanol treatment. Consistent with the above findings, hepatic CXCL1 expression was highly upregulated in patients with alcoholic hepatitis. In a chronic-binge ethanol-feeding model, the TLR2 and TLR9-dependent MyD88-dependent pathway mediates CXCL1 production in hepatocytes and HSCs; the CXCL1 then promotes neutrophil infiltration into the liver via CXCR2, resulting in the development of alcohol-mediated liver injury.
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Malik, Ihtzaz Ahmed, and Giuliano Ramadori. "Interleukin-6-Production Is Responsible for Induction of Hepatic Synthesis of Several Chemokines as Acute-Phase Mediators in Two Animal Models: Possible Significance for Interpretation of Laboratory Changes in Severely Ill Patients." Biology 11, no. 3 (March 18, 2022): 470. http://dx.doi.org/10.3390/biology11030470.
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A mild to moderate increase in acute-phase proteins (APPs) and a decrease in serum albumin levels are detected in hospitalized COVID-19 patients. A similar trend is also observed for acute-phase cytokines (APC), mainly IL6, besides chemokines (e.g., CXCL8 and CCL2). However, the source of the chemokines in these patients at different stages of disease remains to be elucidated. We investigated hepatic gene expression of CXC- and CC-chemokines in a model of a localized extrahepatic aseptic abscess and in a model of septicemia produced by the intramuscular injection of turpentine oil (TO) into each hindlimb or lipopolysaccharide (LPS) intraperitoneally (i.p.) in rats and mice (wild-type (WT) and IL6-KO). Together with a striking increase in the serum IL6 level, strong serum CXCL2 and CXCL8 concentrations were detected. Correspondingly, rapid (2 h) upregulation of CXCL1, CXCL2, CXCL5, and CXCL8 was observed in rat liver after intramuscular TO injection. The induction of the gene expression of CXCL1 and CXCL8 was the fastest and strongest. The hepatic CXC-chemokines behaved like positive APPs that depend on IL6 production by activated macrophages recruited to extrahepatic damaged tissue. Chemokine upregulation was greatly reduced in IL6-KO mice. However, IL6 was dispensable in the LPS–APR model, as massive induction of hepatic chemokines studied was measured in IL6-KO mice.
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Fan, Ning, Shuo Yuan, Yong Hai, Peng Du, Jian Li, Xiaochuan Kong, Wenyi Zhu, Yuzeng Liu, and Lei Zang. "Identifying the potential role of IL-1β in the molecular mechanisms of disc degeneration using gene expression profiling and bioinformatics analysis." Journal of Orthopaedic Surgery 30, no. 1 (January 2022): 230949902110682. http://dx.doi.org/10.1177/23094990211068203.
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Purpose We performed a bioinformatics analysis to identify the key genes that were differentially expressed between degenerative intervertebral disc (IVD) cells with and without exposure to interleukin-1β and explore the related signaling pathways and interaction networks. Methods The microarray data were downloaded from the Gene Expression Omnibus (27,494). Then, analyses of the gene ontology, signaling pathways, and interaction networks for the differentially expressed genes (DEGs) were conducted using tools including the Database for Annotation, Visualization, and Integrated Discovery, Metascape, Gene Set Enrichment Analysis, Search Tool for the Retrieval of Interacting Genes, Cytoscape, Venn method, and packages of the R computing language. Results A total of 260 DEGs were identified, including 161 upregulated and 99 downregulated genes. Gene Ontology annotation analysis showed that these DEGs were mainly associated with the extracellular region, chemotaxis, taxis, cytokine activity, and cytokine receptor binding. A Kyoto Encyclopedia of Genes and Genomes signaling pathway analysis showed that these DEGs were mainly involved in the of cytokine-cytokine receptor interaction, rheumatoid arthritis, tumor necrosis factor signaling pathway, Salmonella infection, and chemokine signaling pathway. The interaction network analysis indicated that 10 hub genes, including CXCL8, CXCL1, CCL20, CXCL2, CXCL5, CXCL3, CXCL6, C3, PF4, and GPER1 may play key roles in IVD degeneration. Conclusions Bioinformatic analysis showed that CXCL8 and other nine key genes may play a role in the development of disc degeneration induced by inflammatory reactions and can be used to identify potential target genes for therapeutic applications in IVD degeneration.
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Cavanagh, P. Craig, Caroline Dunk, Macarena Pampillo, Jacob M. Szereszewski, Jay E. Taylor, Caroline Kahiri, Victor Han, Stephen Lye, Moshmi Bhattacharya, and Andy V. Babwah. "Gonadotropin-releasing hormone-regulated chemokine expression in human placentation." American Journal of Physiology-Cell Physiology 297, no. 1 (July 2009): C17—C27. http://dx.doi.org/10.1152/ajpcell.00013.2009.
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Placental expression of gonadotropin-releasing hormone (GnRH)-I and II, as well as their cognate receptor, coincides with a period of extensive remodeling of the maternal-fetal interface, near the end of the first trimester of pregnancy. To further define the role of GnRH in human placentation, we performed a microarray screen of HTR-8/SVneo trophoblasts to identify GnRH-regulated genes and their roles in placentation. This screen revealed that GnRH regulates the expression of four angiogenic chemokines: CXCL2, CXCL3, CXCL6, and CXCL8. The microarray data were subsequently confirmed by an extensive Q-PCR time-course analysis. CXCL8, a representative chemokine, was selected for further analysis and shown to be strongly expressed by trophoblasts at the maternal-fetal interface of the human placenta, as well as to accumulate in a GnRH-dependent manner in trophoblast-conditioned media in culture. Trophoblasts were subsequently shown to recruit lymphocytes (Jurkat T cells and primary peripheral blood T and uterine natural killer cells) in chemotaxis assays and this was shown to be GnRH dependent. Furthermore, this recruitment was shown to occur via the release of CXCR1/CXCR2 interacting chemokines, such as the CXCLs investigated in this study. This novel regulation of chemokines by GnRH signaling demonstrates the role of GnRH in regulating the recruitment of lymphocytes to the decidua and the possibility of a direct effect on spiral artery remodeling via the release of proangiogenic chemokines and secondary effects via release of angiogenic factors by recruited lymphocytes.
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Tiwari, Nivedita, Amarnath S. Marudamuthu, Yoshikazu Tsukasaki, Mitsuo Ikebe, Jian Fu, and Sreerama Shetty. "p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 6 (March 15, 2016): L496—L506. http://dx.doi.org/10.1152/ajplung.00290.2015.
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We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.
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Li, Yan, Mingqiang Liang, Yuxiang Lin, Jinxing Lv, Minyan Chen, Peng Zhou, Fangmeng Fu, and Chuan Wang. "Transcriptional Expressions of CXCL9/10/12/13 as Prognosis Factors in Breast Cancer." Journal of Oncology 2020 (September 9, 2020): 1–15. http://dx.doi.org/10.1155/2020/4270957.
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CXCLs play critical roles in antitumor immunity by activating tumor-specific immune responses and stimulating tumor proliferation, thus affecting patient outcomes. However, the expression and prognostic values of CXCLs in breast cancer have not been well clarified. The aim of this study was to investigate the impact of CXCLs transcriptional expression on breast cancer patients. Oncomine database, GEPIA (Gene Expression Profiling Interactive Analysis), UALCAN, Kaplan–Meier Plotter, TIMER (Tumor Immune Estimation Resource), and DAVID were used in our study. The transcriptional levels of CXCL9/10/11/13 in breast cancer tissues were significantly elevated while the transcriptional levels of CXCL1/2/3/12 were decreased based on intersections of Oncomine database and GEPIA. Among them, breast cancer patients with high transcriptional levels of CXCL2/9/10/12/13 and low transcriptional level of CXCL3 were associated with a better prognosis. We also found that most of CXCLs expressions are significantly correlated with known prognostic factors, such as patient’s age, major subclasses, individual cancer stages, and nodal metastasis status. In addition, the expression of CXCL9/10/12/13 was also indicated to be correlated with the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). The functions of differentially expressed CXCLs are primarily related to the immune response and cytokine-cytokine receptor interactions. Our results may provide novel evidence of new prognostic or predictive biomarkers for breast cancer patients.
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Piqueras, Bernard, John Connolly, Heidi Freitas, Anna Karolina Palucka, and Jacques Banchereau. "Upon viral exposure, myeloid and plasmacytoid dendritic cells produce 3 waves of distinct chemokines to recruit immune effectors." Blood 107, no. 7 (April 1, 2006): 2613–18. http://dx.doi.org/10.1182/blood-2005-07-2965.
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AbstractHost response to viral infection involves distinct effectors of innate and adaptive immunity, whose mobilization needs to be coordinated to ensure protection. Here we show that influenza virus triggers, in human blood dendritic-cell (DC) subsets (ie, plasmacytoid and myeloid DCs), a coordinated chemokine (CK) secretion program with 3 successive waves. The first one, occurring at early time points (2 to 4 hours), includes CKs potentially attracting effector cells such as neutrophils, cytotoxic T cells, and natural killer (NK) cells (CXCL16, CXCL1, CXCL2, and CXCL3). The second one occurs within 8 to 12 hours and includes CKs attracting effector memory T cells (CXCL8, CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11). The third wave, which occurs after 24 to 48 hours, when DCs have reached the lymphoid organs, includes CCL19, CCL22, and CXCL13, which attract naive T and B lymphocytes. Thus, human blood DC subsets carry a common program of CK production, which allows for a coordinated attraction of the different immune effectors in response to viral infection.
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Marti, Luciana C., Diana Torres Palomino, Camila Bononi Almeida, Denise Cunha Pasqualim, Adriano Cury, Paolo Rogério de Oliveira Salvalaggio, Antonio Luiz Macedo, Patricia Severino, and Luiz Vicente Rizzo. "HUMAN LYMPH NODE DERIVED FIBROBLASTIC RETICULAR CELLS AND THEIR CHEMOKINE EXPRESSION PROFILE AFTER AN INFLAMMATORY STIMULUS." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 51.11. http://dx.doi.org/10.4049/jimmunol.196.supp.51.11.
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Abstract Lymph node is a secondary lymphoid organ with highly organized and compartmentalized structure. Fibroblastic reticular cells (FRC) integrate LN structure, and are characterized by podoplanin expression (PDPN) and lack of CD31. FRCs are involved in several immune response processes but the mechanism is still under investigation. Another cell population present in the lymph node is the one lacking PDPN and CD31, so called, double negative population (DNC). FRCs and DNCs are described as chemokines producers, controlling migratory pattern and positioning of immune cells during homeostasis or inflammation. We evaluate the gene expression of human FRCs and DNCs after an inflammatory stimulus. Lymph nodes were obtained from 04 patients with different clinical diagnosis submitted to surgical procedures. All patients signed an informed consent (Approved by Ethic Committee - CAAE: 07768712.4.0000.0071). All lymph nodes were analyzed by histopathology, they were also enzymatic digested. Cells were characterized and sorted in two populations FRCs and DNCs. These cells were maintained without stimuli or stimulated with TNFα + IL-1β for 24hours. Next, RNA was extracted; gene expression was characterized using DNA Microarray. Our results demonstrate up-regulation of chemokines such as CCL2, CCL3, CCL5, CCL7 CXCL1, CXCL2, CXCL8 and CXL10 (p<0.05) in both cells subsets after inflammatory stimuli, the secretion enhancement of CCL2, CCL20 and CXCL8 was confirmed by ELISA. The up-regulated expression of CCL3L3, CCL11, CCL13, CXCL5, CXCL6 only by FRCs and CCL8, CXCL3 only by DNCs, may link these cells to additional properties that need to be further investigated. These results show that FRC and DNC positively respond to an inflammatory stimulus.
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Liu, Kaisheng, Minshan Lai, Shaoxiang Wang, Kai Zheng, Shouxia Xie, and Xiao Wang. "Construction of a CXC Chemokine-Based Prediction Model for the Prognosis of Colon Cancer." BioMed Research International 2020 (March 31, 2020): 1–12. http://dx.doi.org/10.1155/2020/6107865.
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Colon cancer is the third most common cancer, with a high incidence and mortality. Construction of a specific and sensitive prediction model for prognosis is urgently needed. In this study, profiles of patients with colon cancer with clinical and gene expression data were downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (TCGA). CXC chemokines in patients with colon cancer were investigated by differential expression gene analysis, overall survival analysis, receiver operating characteristic analysis, gene set enrichment analysis (GSEA), and weighted gene coexpression network analysis. CXCL1, CXCL2, CXCL3, and CXCL11 were upregulated in patients with colon cancer and significantly correlated with prognosis. The area under curve (AUC) of the multigene forecast model of CXCL1, CXCL11, CXCL2, and CXCL3 was 0.705 in the GSE41258 dataset and 0.624 in TCGA. The prediction model was constructed using the risk score of the multigene model and three clinicopathological risk factors and exhibited 92.6% and 91.8% accuracy in predicting 3-year and 5-year overall survival of patients with colon cancer, respectively. In addition, by GSEA, expression of CXCL1, CXCL11, CXCL2, and CXCL3 was correlated with several signaling pathways, including NOD-like receptor, oxidative phosphorylation, mTORC1, interferon-gamma response, and IL6/JAK/STAT3 pathways. Patients with colon cancer will benefit from this prediction model for prognosis, and this will pave the way to improve the survival rate and optimize treatment for colon cancer.
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Arsentieva, N. A., N. E. Lyubimova, O. K. Batsunov, A. V. Semenov, and A. A. Totolian. "Analysis of blood plasma cytokine profile in healthy residents of the Republic of Guinea." Medical Immunology (Russia) 22, no. 4 (August 7, 2020): 765–78. http://dx.doi.org/10.15789/1563-0625-aob-2073.
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The cytokine system is a large group of humoral factors produced by immune cells and involved in the pathogenesis of most human diseases. To assess the significance of changes in cytokines/chemokines under pathological conditions, appropriate reference values are required for healthy people. As known from existing literature, most studies of various cytokine/chemokine concentrations in blood plasma were performed in healthy subjects from Western Europe and North America. Certain inter-population differences are known, with respect to production of distinct cytokines in different racial and national groups. Only single studies concern normal levels of distinct cytokines in blood plasma of healthy African residents. The purpose of this study was to determine the blood plasma cytokine profile in healthy residents of the Republic of Guinea (RG), and to establish normal cytokine values.We have examined 24 healthy RG residents and 23 residents of St. Petersburg. Concentrations of 40 cytokines/chemokines were determined in blood plasma. The study was performed using multiplex analysis by xMAP technology.The following cytokine/chemokine levels were significantly increased in the blood plasma of the RG residents: IFNγ, IL-2, IL-4, IL-6, IL-10, TNFα, CCL1/I-309, CCL3/MIP-1α, CCL7/MCP-3, CCL17/ TARC, CCL19/MIP-3β, CCL20/MIP-3α, CCL21/6Ckine, CXCL2/Gro-β, CXCL5/ENA-78, CXCL6/ GCP-2, CXCL9/MiG, CX3CL1/Fractalkine (р < 0.001). For the CCL8/MCP-2, CCL22/MDC, CXCL1/ Gro-α and CXCL12/SDF-1α+β chemokines a trend for increased concentration was revealed, in comparison with residents of St. Petersburg (р < 0.05). Moreover, the levels of CCL23/MPIF-1 and MIF were significantly lower (р < 0.0001) in the RG residents. There was a tendency for decreased levels (р < 0.05) for CCL2/MCP-1 and CCL24/Eotaxin-2 chemokines in blood plasma taken from RG residents. There were no differences in levels of cytokines/chemokines for the studied groups: GM-CSF, IL-1β, IL-16, CCL11/Eotaxin, CCL13/MCP-4, CCL15/Leukotactin-1, CCL25/TECK, CCL26/Eotaxin-3, CCL27/CTACK, CXCL8/IL-8, CXCL10/IP-10, CXCL11/I-TAC, CXCL13/BCA, and CXCL16/SCYB16. Hence, this study has presented for the first time the normal limits for a wide range of cytokines/chemokines in blood plasma of the African inhabitants. Interpopulation differences were found, including those for constitutive chemokines. Different levels of CCL19/ MIP-3β and CCL21/6Ckine chemokines (the CCR7 receptor ligands) for the two populations may indirectly indicate the physiological features of T-cell maturation. Increased levels of CXCR2 receptor ligands in the blood plasma of Guineans, i.e., CXCL2/Gro-β, CXCL5/ENA-78 and CXCL6/GCP-2, may be due to additional function of these chemokines as ligands for atypical DARC chemokine receptor, which neutralizes chemokines from the blood flow, whereas 95% of West Africans have mutations in the DARC gene and do not express this receptor. Increased levels of proinflammatory IL-6 and TNFα cytokines, and chemokine CCL20/MIP-3α in blood plasma from RG residents may suggest inflammatory processes in the liver, since 100% of the examined Guineans had antibodies against the hepatitis A virus, 48% had antibodies to hepatitis B virus (anti-HBs), and 12% had antibodies against hepatitis C virus. In summary, the differences in cytokine/chemokine level may be related to specific environment, circulation of infectious diseases, composition of intestinal, skin and mucosal microbiota, as well as distinct genetic features.
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Burke, Susan J., Danhong Lu, Tim E. Sparer, Thomas Masi, Matthew R. Goff, Michael D. Karlstad, and J. Jason Collier. "NF-κB and STAT1 control CXCL1 and CXCL2 gene transcription." American Journal of Physiology-Endocrinology and Metabolism 306, no. 2 (January 15, 2014): E131—E149. http://dx.doi.org/10.1152/ajpendo.00347.2013.
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Diabetes mellitus results from immune cell invasion into pancreatic islets of Langerhans, eventually leading to selective destruction of the insulin-producing β-cells. How this process is initiated is not well understood. In this study, we investigated the regulation of the CXCL1 and CXCL2 genes, which encode proteins that promote migration of CXCR2+ cells, such as neutrophils, toward secreting tissue. Herein, we found that IL-1β markedly enhanced the expression of the CXCL1 and CXCL2 genes in rat islets and β-cell lines, which resulted in increased secretion of each of these proteins. CXCL1 and CXCL2 also stimulated the expression of specific integrin proteins on the surface of human neutrophils. Mutation of a consensus NF-κB genomic sequence present in both gene promoters reduced the ability of IL-1β to promote transcription. In addition, IL-1β induced binding of the p65 and p50 subunits of NF-κB to these consensus κB regulatory elements as well as to additional κB sites located near the core promoter regions of each gene. Additionally, serine-phosphorylated STAT1 bound to the promoters of the CXCL1 and CXCL2 genes. We further found that IL-1β induced specific posttranslational modifications to histone H3 in a time frame congruent with transcription factor binding and transcript accumulation. We conclude that IL-1β-mediated regulation of the CXCL1 and CXCL2 genes in pancreatic β-cells requires stimulus-induced changes in histone chemical modifications, recruitment of the NF-κB and STAT1 transcription factors to genomic regulatory sequences within the proximal gene promoters, and increases in phosphorylated forms of RNA polymerase II.
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Furue, Masutaka, Kazuhisa Furue, Gaku Tsuji, and Takeshi Nakahara. "Interleukin-17A and Keratinocytes in Psoriasis." International Journal of Molecular Sciences 21, no. 4 (February 13, 2020): 1275. http://dx.doi.org/10.3390/ijms21041275.
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The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6+ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6+ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.
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Cai, Baiyi, Carlene L. Zindl, Daniel J. Silberger, David A. Figge, Jeffery R. Singer, Simon F. Merz, Matthias Gunzer, and Casey T. Weaver. "Temporal changes in cellular sources of CXC chemokines control neutrophil recruitment during Citrobacter rodentium infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 158.22. http://dx.doi.org/10.4049/jimmunol.204.supp.158.22.
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Abstract Enteropathogenic E. coli (EPEC) is one of the leading causes of diarrheal disease among children. Citrobacter rodentium (C.r) is a mouse model for EPEC and neutrophils have been found to be required for effective host protection against C.r. Yet details of the cellular sources that control neutrophil recruitment during C.r infection are poorly understood. Here we have found that C.r infection promotes neutrophil recruitment that is limited to distal colon where C.r colonizes. C.r infection induces the neutrophil-recruiting chemokines CXCL1, CXCL2 and CXCL5 in distal colon. Early in infection (D4) intestinal epithelial cells serve as the dominant source of CXCL1/2/5. However, later in infection (D8) neutrophils also provide CXCL1 and CXCL2, but fail to produce CXCL5, production of which is sustained in superficial epithelial cells. These findings support a model in which production of neutrophil-attracting chemokines is initiated in the infected epithelium and is amplified in a feedforward manner by incoming neutrophils. However, the unique production of CXCL5 by epithelial cells may be essential to recruit neutrophils to the mucosal surface, which C.r colonizes during infection.
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Laudanski, Piotr, Adam Lemancewicz, Pawel Kuc, Karol Charkiewicz, Barbara Ramotowska, Malgorzata Kretowska, Elwira Jasinska, et al. "Chemokines Profiling of Patients with Preterm Birth." Mediators of Inflammation 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/185758.
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Introduction.Nowadays it is thought that the main cause of premature birth is subclinical infection. However, none of the currently used methods provide effective prevention to preterm labor. The aim of the study was to determine the concentration of selected chemokines in sera of patients with premature birth without clinical signs of infection (n=62), threatened preterm labor (n=47), and term births (n=28).Method.To assess the concentration of chemokines in the blood serum, we used a multiplex method, which allows the simultaneous determination of 40 chemokines per sample. The sets consist of the following chemokines: 6Ckine/CCL21, Axl, BTC, CCL28, CTACK/CCL27, CXCL16, ENA-78/CXCL5, Eotaxin-3/CCL26, GCP-2/CXC, GRO (GROα/CXCL1, GROβ/CXCL2 and GROγ/CXCL3), HCC-1/CCL14, HCC-4/CCL16, IL-9, IL-17F, IL18-BPa, IL-28A, IL-29, IL-31, IP-10/CXCL10, I-TAC/CXCL11, LIF, LIGHT/TNFSF14, Lymphotactin/XCL1, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13, MDC/CCL22, MIF, MIP-3α/CCL20, MIP-3-β/CCL19, MPIF-1/CCL23, NAP-2/CXCL7, MSPα, OPN, PARC/CCL18, PF4, SDF-1/CXCL12, TARC/CCL17, TECK/CCL25, and TSLP.Results.We showed possible implication of 4 chemokines, that is, HCC-4, I-TAC, MIP-3α, and TARC in women with symptoms of preterm delivery.Conclusion.On the basis of our findings, it seems that the chemokines may play role in the pathogenesis of preterm labor. Defining their potential as biochemical markers of preterm birth requires further investigation on larger group of patients.
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Carlson, Thaddeus, Mark Kroenke, Praveen Rao, Thomas E. Lane, and Benjamin Segal. "The Th17–ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease." Journal of Experimental Medicine 205, no. 4 (March 17, 2008): 811–23. http://dx.doi.org/10.1084/jem.20072404.
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The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.
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Bardi, Gina, Numan Al-Rayan, Jamaal Richie, Kavitha Yaddanapudi, and Joshua Hood. "Detection of Inflammation-Related Melanoma Small Extracellular Vesicle (sEV) mRNA Content Using Primary Melanocyte sEVs as a Reference." International Journal of Molecular Sciences 20, no. 5 (March 12, 2019): 1235. http://dx.doi.org/10.3390/ijms20051235.
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Melanoma-derived small extracellular vesicles (sEVs) participate in tumor pathogenesis. Tumor pathogenesis is highly dependent on inflammatory processes. Given the potential for melanoma sEVs to carry tumor biomarkers, we explored the hypothesis that they may contain inflammation-related mRNA content. Biophysical characterization showed that human primary melanocyte-derived sEVs trended toward being smaller and having less negative (more neutral) zeta potential than human melanoma sEVs (A-375, SKMEL-28, and C-32). Using primary melanocyte sEVs as the control population, RT-qPCR array results demonstrated similarities and differences in gene expression between melanoma sEV types. Upregulation of pro-angiogenic chemokine ligand CXCL1, CXCL2, and CXCL8 mRNAs in A-375 and SKMEL-28 melanoma sEVs was the most consistent finding. This paralleled increased production of CXCL1, CXCL2, and CXCL8 proteins by A-375 and SKMEL-28 sEV source cells. Overall, the use of primary melanocyte sEVs as a control sEV reference population facilitated the detection of inflammation-related melanoma sEV mRNA content.
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Du, Chunmei, Yiguang Zhao, Kun Wang, Xuemei Nan, Ruipeng Chen, and Benhai Xiong. "Effects of Milk-Derived Extracellular Vesicles on the Colonic Transcriptome and Proteome in Murine Model." Nutrients 14, no. 15 (July 26, 2022): 3057. http://dx.doi.org/10.3390/nu14153057.
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Evidence shows that effective nutritional intervention can prevent or mitigate the risk and morbidity of inflammatory bowel disease (IBD). Bovine milk extracellular vesicles (mEVs), a major bioactive constituent of milk, play an important role in maintaining intestinal health. The aims of this study were to assess the effects of mEV pre-supplementation on the colonic transcriptome and proteome in dextran sulphate sodium (DSS)-induced acute colitis, in order to understand the underlying molecular mechanisms of mEV protection against acute colitis. Our results revealed that dietary mEV supplementation alleviated the severity of acute colitis, as evidenced by the reduced disease activity index scores, histological damage, and infiltration of inflammatory cells. In addition, transcriptome profiling analysis found that oral mEVs significantly reduced the expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17A and IL-33), chemokine ligands (CXCL1, CXCL2, CXCL3, CXCL5, CCL3 and CCL11) and chemokine receptors (CXCR2 and CCR3). Moreover, oral mEVs up-regulated 109 proteins and down-regulated 150 proteins in the DSS-induced murine model, which were involved in modulating amino acid metabolism and lipid metabolism. Collectively, this study might provide new insights for identifying potential targets for the therapeutic effects of mEVs on colitis.
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Huang, Alex, and Jay Myers. "Live two-photon imaging reveals distinct contribution of neutrophilic and stromal Toll-like receptor 4 in hyper-acute bone marrow response to systemic lipopolysaccharide insult (INC5P.324)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 120.4. http://dx.doi.org/10.4049/jimmunol.192.supp.120.4.
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Abstract Produced in the bone marrow (BM) in large quantities, neutrophils are rapidly mobilized and released into circulation in response to inflammation and infection. How BM neutrophils are released as a result of CXCL12 and CXCL1/CXCL2 gradients have been studied at a long time scale (hours to days) following lipopolysaccharide (LPS) challenge. However, little is known about how neutrophil and BM stroma react during the hyper-acute (minutes to hours) phase. We performed intravital microscopy on mice that express GFP under the Lysozyme M (LysM) promoter. BM chimeras were generated to differentiate TLR4-mediated responses in hematopoietic and radio-resistant stroma. We observed a 2.5-fold increase in the speed and the formation of dynamic cellular clusters in 50% of BM neutrophils 30-60 minutes after LPS injection. The neutrophils achieved a peak average speed of 8.4 um/min, accompanied by their disappearance into circulation as evidenced by a 40% reduction in the GFP fluorescence after 90 minutes. BM chimera experiments revealed that while intra-marrow migration and cellular clustering are dependent on TLR4 signaling in neutrophils, their release into systemic circulation is dependent on stromal TLR4 signaling. Blocking CXCR2 signaling had the same effect as chimeras expressing TLR4-defective stroma, further revealing that BM stroma modulate TLR4-mediated neutrophil mobilization and release via CXCL1/CXCL2 chemokine signaling during the hyper-acute phase of marrow response to LPS.
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Deftu, Antonia-Teona, Alexandru-Florian Deftu, and Violeta Ristoiu. "Long-term incubation with CXCL2, but not with CXCL1, alters the kinetics of TRPV1 receptors in cultured dorsal root ganglia neurons." Archives of Biological Sciences 69, no. 1 (2017): 53–59. http://dx.doi.org/10.2298/abs160513074d.
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CXCL1 and CXCL2 are homologous chemokines that can be upregulated in different pathological conditions, affecting among other targets, neuronal ionic channels or receptors. TRPV1 is a polymodal nociceptor expressed in both dorsal root and trigeminal ganglia neurons. According to existing data, short-term incubation with CXCL1 can reduce TRPV1 desensitization, however, the long-term modulatory effect of both CXCL1 and CXCL2 on this receptor is less known. In the present study we investigated the influence of overnight incubation with 1.5 nM CXCL1 or CXCL2 on the functioning of TRPV1 receptors expressed in cultured dorsal root ganglia neurons. Calcium imaging and patch-clamp recordings showed that under the same experimental conditions and at the same concentration, only CXCL2 significantly decreased the TRPV1 current and increased its desensitization rate, whereas CXCL1 had no effect. This study proposes a different contribution of CXCL1 and CXCL2 to the modulation of TRPV1-mediated processes, in spite of their highly homologous sequence.
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Semple, Bridgette D., Thomas Kossmann, and Maria Cristina Morganti-Kossmann. "Role of Chemokines in CNS Health and Pathology: A Focus on the CCL2/CCR2 and CXCL8/CXCR2 Networks." Journal of Cerebral Blood Flow & Metabolism 30, no. 3 (November 11, 2009): 459–73. http://dx.doi.org/10.1038/jcbfm.2009.240.
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Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
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Navas, Adriana, Deninson Alejandro Vargas, Marina Freudzon, Diane McMahon-Pratt, Nancy Gore Saravia, and María Adelaida Gómez. "Chronicity of Dermal Leishmaniasis Caused by Leishmania panamensis Is Associated with Parasite-Mediated Induction of Chemokine Gene Expression." Infection and Immunity 82, no. 7 (April 21, 2014): 2872–80. http://dx.doi.org/10.1128/iai.01133-13.
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ABSTRACTChronic tegumentary leishmaniasis is characterized by a scarcity of parasites in lesions and a heightened inflammatory response. Deregulated and hyperactive inflammation contributes to tissue damage and parasite persistence. The mechanisms by which immune cells are recruited to the lesion and their relationship to clinical outcomes remain elusive. We examined the expression levels of chemokines and their receptors in relation to clinical outcome in dermal leishmaniasis caused byLeishmania (Viannia) panamensis. Primary macrophages from healthy donors were infected withL. panamensisstrains isolated from self-healing patients (n= 4) and those presenting chronic disease (n= 5). A consistent pattern of upregulation of neutrophil (cxcl1,cxcl2,cxcl5, andcxcl8/il-8) and monocyte (ccl2,ccl7,ccl8,cxcl3, andcxcl10) chemotactic chemokines andccr1andccr5receptor genes, evaluated by reverse transcription-quantitative PCR (qRT-PCR), was observed upon infection with strains from patients with chronic dermal leishmaniasis; induction of CXCL5 and CCL8 was corroborated at the protein level. No apparent upregulation was elicited in macrophages infected with strains from self-healing patients. Expression levels ofccl8,cxcl2,cxcl3, andcxcl5in lesion biopsy specimens from patients with chronic cutaneous leishmaniasis (CL) were compared to those in biopsy specimens from Montenegro skin tests of individuals with asymptomatic infection. Increased expression levels ofcxcl5(P< 0.05),ccl8, andcxcl3were corroborated in chronic CL lesions. Our study revealed a dichotomy in macrophage chemokine gene expression elicited byL. panamensisstrains from patients with self-healing disease and those presenting chronic disease, consistent with parasite-mediated hyperactivation of the inflammatory response driving chronicity. The predominant upregulation of neutrophil and monocyte chemoattractants indicates novel mechanisms of sustained inflammatory activation and may provide new therapeutic targets against chronic dermal leishmaniasis.
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Takikawa, Tetsuya, Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Fumiya Kataoka, Akira Sasaki, and Atsushi Masamune. "Senescent Human Pancreatic Stellate Cells Secrete CXCR2 Agonist CXCLs to Promote Proliferation and Migration of Human Pancreatic Cancer AsPC-1 and MIAPaCa-2 Cell Lines." International Journal of Molecular Sciences 23, no. 16 (August 17, 2022): 9275. http://dx.doi.org/10.3390/ijms23169275.
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Interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) play an important role in the progression of pancreatic cancer. Recent studies have shown that cellular senescence and senescence-associated secretory phenotype factors play roles in the progression of cancer. This study aimed to clarify the effects of senescence-induced PSCs on pancreatic cancer cells. Senescence was induced in primary-cultured human PSCs (hPSCs) through treatment with hydrogen peroxide or gemcitabine. Microarray and Gene Ontology analyses showed the alterations in genes and pathways related to cellular senescence and senescence-associated secretory phenotype factors, including the upregulation of C-X-C motif chemokine ligand (CXCL)-1, CXCL2, and CXCL3 through the induction of senescence in hPSCs. Conditioned media of senescent hPSCs increased the proliferation—as found in an assessment with a BrdU incorporation assay—and migration—as found in an assessment with wound-healing and two-chamber assays—of pancreatic cancer AsPC-1 and MIAPaca-2 cell lines. SB225002, a selective CXCR2 antagonist, and SCH-527123, a CXCR1/CXCR2 antagonist, attenuated the effects of conditioned media of senescent hPSCs on the proliferation and migration of pancreatic cancer cells. These results suggest a role of CXCLs as senescence-associated secretory phenotype factors in the interaction between senescent hPSCs and pancreatic cancer cells. Senescent PSCs might be novel therapeutic targets for pancreatic cancer.
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Wang, Danlan, Yuanfang Luo, Yonglian Guo, Guohao Li, and Fan Li. "A-kinase interacting protein 1, a potential biomarker associated with advanced tumor features and CXCL1/2 in prostate cancer." International Journal of Biological Markers 35, no. 2 (April 27, 2020): 74–81. http://dx.doi.org/10.1177/1724600820914944.
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Objective: This study aimed to investigate the correlation of A-kinase interacting protein 1 (AKIP1) with chemokine (C-X-C motif) ligand 1 (CXCL1) and CXCL2, as well as their associations with clinical characteristics and prognosis in prostate cancer patients. Methods: A total of 248 eligible prostate cancer patients who underwent surgery were consecutively recruited, and tumor tissues were collected during the surgery. AKIP1, CXCL1, and CXCL2 expression in tumor tissues were assessed by immunohistochemistry. Disease-free survival and overall survival were recorded, and the median follow-up time was 27 months. Results: The proportion of patients with AKIP1, CXCL1, and CXCL2 high expression was 56.5%, 63.7%, and 56.9%, respectively. Additionally, AKIP1 expression positively correlated with CXCL1 expression ( P<0.001) and CXCL2 expression ( P<0.001), and CXCL1 expression was positively associated with CXCL2 expression ( P<0.001). Furthermore, AKIP1 expression positively correlated with pathological T stage ( P<0.001) and pathological N stage ( P=0.003). CXCL1 expression was positively associated with pathological T stage ( P<0.001) and pathological N stage ( P<0.001) as well. However, the CXCL2 expression only positively correlated with pathological T stage ( P=0.002). Also, AKIP1 high expression correlated with worse disease-free survival ( P=0.049) and OS ( P=0.013), and CXCL1 high expression was associated with unfavorable disease-free survival ( P=0.023) but not overall survival ( P=0.052). CXCL2 expression was not correlated with disease-free survival ( P=0.083) or overall survival ( P=0.065). Multivariate Cox’s regression disclosed that AKIP1 high expression independently predicted worse overall survival ( P=0.009). Conclusion: AKIP1 positively associates with CXCL1/2 and is a potential biomarker for disease monitoring as well as prognosis in prostate cancer.
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Rainard, P. "Consequences of Interference of Milk with Chemoattractants for Enzyme-Linked Immunosorbent Assay Quantifications." Clinical and Vaccine Immunology 17, no. 5 (March 17, 2010): 848–52. http://dx.doi.org/10.1128/cvi.00447-09.
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ABSTRACT Concentrations of the chemoattractants CXCL1, CXCL2, CXCL3, CXCL8, and C5a in milk were reduced by the preparation of milk whey by high-speed centrifugation or with rennet. About half of the chemoattractants (35 to 65%) were associated with the casein micelle sediment, except when whey was prepared by acidification. Consequently, quantification of chemoattractants should be carried out preferentially with skimmed milk samples or, whenever whey is needed, with acidic whey samples. The interference of milk or milk whey with the enzyme-linked immunosorbent assays (ELISAs) used to quantify the chemoattractants was moderate, as long as tetramethylbenzidine (TMB), not ABTS [2,2′-azino-bis-(3-ethylbenzthiazoline-sulfonate)], was used as the substrate of peroxidase. These considerations will help to assess more precisely a component of the immune response of the mammary gland to infection.
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Li, Heliang, Linbin Yang, and Erwei Song. "Abstract 628: Liver macrophages promote breast cancer liver metastasis through migrating neutrophils and initiating NETosis." Cancer Research 83, no. 7_Supplement (April 4, 2023): 628. http://dx.doi.org/10.1158/1538-7445.am2023-628.
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Abstract Neutrophils extracellular traps (NETs), which are DNA scaffolds in complex with granule proteins, could be detected in the pre-metastatic liver niches and were associated with a poor survival in breast cancer patients. However, the mechanisms of neutrophils infiltration and NETs formation in the pre-metastatic liver tissues remain poorly understood. Here, we dynamically characterized the liver micro-environment of normal and 4T1-bearing BALB/C mouse models with or without liver metastasis by the single cell RNA sequencing. Interestingly, we found that CXCL1 and CXCL2, derived from the liver macrophages, were dramatically elevated in pre-metastatic livers and induced the infiltration of peripheral neutrophils by CXCR2. Besides, liver macrophages were educated by cancer cells-derived cathepsin C to secrete the CXCL1 and CXCL2. Furthermore, we identified that the complement signals were over-activated in pre-metastatic livers and induced neutrophils to NETosis. Therapeutically, targeting CXCL1, CXCL2 and complement signals could inhibit the NET formation and effectively reduce breast cancer liver metastasis. Citation Format: Heliang Li, Linbin Yang, Erwei Song. Liver macrophages promote breast cancer liver metastasis through migrating neutrophils and initiating NETosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 628.
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Oliveira, Thiago Henrique Caldeira, Vincent Vanheule, Sofie Vandendriessche, Fariba Poosti, Mauro Martins Teixeira, Paul Proost, Mieke Gouwy, and Pedro Elias Marques. "The GAG-Binding Peptide MIG30 Protects against Liver Ischemia-Reperfusion in Mice." International Journal of Molecular Sciences 23, no. 17 (August 26, 2022): 9715. http://dx.doi.org/10.3390/ijms23179715.
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Ischemia-reperfusion injury (IRI) drives graft rejection and is the main cause of mortality after liver transplantation. During IRI, an intense inflammatory response marked by chemokine production and neutrophil recruitment occurs. However, few strategies are available to restrain this excessive response. Here, we aimed to interfere with chemokine function during IRI in order to disrupt neutrophil recruitment to the injured liver. For this, we utilized a potent glycosaminoglycan (GAG)-binding peptide containing the 30 C-terminal amino acids of CXCL9 (MIG30) that is able to inhibit the binding of chemokines to GAGs in vitro. We observed that mice subjected to IRI and treated with MIG30 presented significantly lower liver injury and dysfunction as compared to vehicle-treated mice. Moreover, the levels of chemokines CXCL1, CXCL2 and CXCL6 and of proinflammatory cytokines TNF-α and IL-6 were significantly reduced in MIG30-treated mice. These events were associated with a marked inhibition of neutrophil recruitment to the liver during IRI. Lastly, we observed that MIG30 is unable to affect leukocytes directly nor to alter the stimulation by either CXCL8 or lipopolysaccharide (LPS), suggesting that its protective properties derive from its ability to inhibit chemokine activity in vivo. We conclude that MIG30 holds promise as a strategy to treat liver IRI and inflammation.
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Urbantat, Ruth M., Peter Vajkoczy, and Susan Brandenburg. "Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma." Cancers 13, no. 12 (June 15, 2021): 2983. http://dx.doi.org/10.3390/cancers13122983.
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With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.
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Miura, Koshiro, and Yasuko Rikihisa. "Liver Transcriptome Profiles Associated with Strain-Specific Ehrlichia chaffeensis-Induced Hepatitis in SCID Mice." Infection and Immunity 77, no. 1 (November 10, 2008): 245–54. http://dx.doi.org/10.1128/iai.00979-08.
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ABSTRACT Infection of humans with Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis, can cause hepatitis of various levels of severity. When the three human isolates of E. chaffeensis, each belonging to a different genogroup, are inoculated into severe combined immunodeficiency mice, the order of severity of clinical signs and bacterial burden detected in the liver is as follows (from greatest to least severity and highest to lowest burden): strain Wakulla, followed by strain Liberty, followed by strain Arkansas. In this article, we used microarray analysis to define transcriptional profiles characteristic of the histopathological features in the mouse liver. Cytokine and chemokine profiles and their receptor profiles were strikingly different among the three strains of E. chaffeensis: gamma interferon, CCL5, CXCL1, CXCL2, CXCL7, CXCL9, interleukin 2 receptor gamma (IL2Rγ), IL21R, CCR2, and CXCR6 were highly upregulated with strain Arkansas; and tumor necrosis factor (TNF), CCL2, CCL3, CCL5, CCL6, CCL12, CCL20, CXCL2, CXCL7, CXCL9, CXCL13, TNF receptor superfamily 9 (TNFRSF9), TNFRSF13β, IL1R2, IL2Rγ, IL20Rβ, IL21R, CCR1, CCR2, and CXCR4 were highly upregulated with strain Wakulla. With strain Liberty, only CXCL13 was highly upregulated, and IL13Rα2 was downregulated. In livers infected with the Arkansas strain, monocytes/macrophages and NK cells were enriched in the granulomas and an increase in NK cell marker mRNAs was detected. Livers infected with the Wakulla strain displayed infiltration of significantly more neutrophils and an increase in neutrophil marker mRNAs. Genes commonly upregulated in liver tissue infected with the three strains are other host innate immune and inflammatory response genes, including those encoding several acute-phase proteins. Genes downregulated commonly are related to host physiologic functions. The results suggest that marked modulation of host cytokine and chemokine profiles by E. chaffeensis strains underlies the distinct host liver disease.
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Lepsenyi, Mattias, Nader Algethami, Amr A. Al-Haidari, Anwar Algaber, Ingvar Syk, Milladur Rahman, and Henrik Thorlacius. "CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells." Clinical & Experimental Metastasis 38, no. 4 (June 11, 2021): 401–10. http://dx.doi.org/10.1007/s10585-021-10103-0.
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AbstractPeritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.
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Mayslich, Constance, Philippe Alain Grange, Mathieu Castela, Anne Geneviève Marcelin, Vincent Calvez, and Nicolas Dupin. "Characterization of a Cutibacterium acnes Camp Factor 1-Related Peptide as a New TLR-2 Modulator in In Vitro and Ex Vivo Models of Inflammation." International Journal of Molecular Sciences 23, no. 9 (May 3, 2022): 5065. http://dx.doi.org/10.3390/ijms23095065.
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Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.
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Zychowska, Magdalena, Ewelina Rojewska, Dominika Pilat, and Joanna Mika. "The Role of Some Chemokines from the CXC Subfamily in a Mouse Model of Diabetic Neuropathy." Journal of Diabetes Research 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/750182.
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The mechanism involved in the development of diabetic neuropathy is complex. Currently, it is thought that chemokines play an important role in this process. The aim of this study was to determine how the level of some chemokines from the CXC subfamily varies in diabetic neuropathy and how the chemokines affect nociceptive transmission. A single intraperitoneal (i.p.) injection of streptozotocin (STZ; 200 mg/kg) resulted in an increased plasma glucose. The development of allodynia and hyperalgesia was measured at day 7 after STZ administration. Using Antibody Array techniques, the increases in CXCL1 (KC), CXCL5 (LIX), CXCL9 (MIG), and CXCL12 (SDF-1) protein levels were detected in STZ-injected mice. No changes in CXCL11 (I-TAC) or CXCL13 (BLC) protein levels were observed. The single intrathecal (i.t.) administration of CXCL1, CXCL5, CXCL9, and CXCL12 (each in doses of 10, 100, and 500 ng/5 μL) shows their pronociceptive properties as measured 1, 4, and 24 hours after injection using the tail-flick, von Frey, and cold plate tests. These findings indicate that the chemokines CXCL1, CXCL5, CXCL9, and CXCL12 are important in nociceptive transmission and may play a role in the development of diabetic neuropathy.
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Ritzman, Anna M., Jennifer M. Hughes-Hanks, Victoria A. Blaho, Laura E. Wax, William J. Mitchell, and Charles R. Brown. "The Chemokine Receptor CXCR2 Ligand KC (CXCL1) Mediates Neutrophil Recruitment and Is Critical for Development of Experimental Lyme Arthritis and Carditis." Infection and Immunity 78, no. 11 (September 7, 2010): 4593–600. http://dx.doi.org/10.1128/iai.00798-10.
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ABSTRACT Deletion of the chemokine receptor CXCR2 prevents the recruitment of neutrophils into tissues and subsequent development of experimental Lyme arthritis. Following footpad inoculation of Borrelia burgdorferi, the agent of Lyme disease, expression of the CXCR2 ligand KC (CXCL1) is highly upregulated in the joints of arthritis-susceptible mice and is likely to play an important role in the recruitment of neutrophils to the site of infection. To test this hypothesis, we infected C3H KC−/− mice with B. burgdorferi and followed the development of arthritis and carditis. Ankle swelling was significantly attenuated during the peak of arthritis in the KC−/− mice. Arthritis severity scores were significantly lower in the KC−/− mice on days 11 and 21 postinfection, with fewer neutrophils present in the inflammatory lesions. Cardiac lesions were also significantly decreased in KC−/− mice at day 21 postinfection. There were, however, no differences between C3H wild-type and KC−/− mice in spirochete clearance from tissues. Two other CXCR2 ligands, LIX (CXCL5) and MIP-2 (CXCL2), were not increased to compensate for the loss of KC, and the production of several innate cytokines was unaltered. These results demonstrate that KC plays a critical nonredundant role in the development of experimental Lyme arthritis and carditis via CXCR2-mediated recruitment of neutrophils into the site of infection.
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Urbantat, Ruth, Anne Blank, Irina Kremenetskaia, Peter Vajkoczy, Güliz Acker, and Susan Brandenburg. "The CXCL2/IL8/CXCR2 Pathway Is Relevant for Brain Tumor Malignancy and Endothelial Cell Function." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2634. http://dx.doi.org/10.3390/ijms22052634.
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We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.
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Bian, Jing, Jianyang Fu, Xin Wang, Jihye Lee, Gagandeep Brar, Freddy E. Escorcia, Maggie Cam, and Changqing Xie. "Characterization of Immunogenicity of Malignant Cells with Stemness in Intrahepatic Cholangiocarcinoma by Single-Cell RNA Sequencing." Stem Cells International 2022 (April 29, 2022): 1–14. http://dx.doi.org/10.1155/2022/3558200.
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Cancer stem cells (CSCs) are responsible for long-term maintenance of tumors and thought to play a role in treatment resistance. The interaction between stemness and immunogenicity of CSCs in the intrahepatic cholangiocarcinoma (iCCA) is largely unknown. Here, we used single-cell transcriptomic data to study immunogenicity of malignant cells in human iCCA. Using an established computerized method CytoTRACE, we found significant heterogeneity in stemness/differentiation states among malignant cells. We demonstrated that the high stemness malignant cells express much lower levels of major histocompatibility complex II molecules when compared to low stemness malignant cells, suggesting a role of immune evasion in high stemness malignant cells. In addition, high stemness malignant iCCA cells exhibited significant expression of certain cytokine members, including CCL2, CCL20, CXCL1, CXCL2, CXCL6, CXCL8, TNFRSF12A, and IL6ST, indicating communication with surrounding immune cells. These results indicate that high stemness malignant cells retain their intrinsic immunological feature that facilitate the escape of immune surveillance.
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Link, Daniel. "Mechanisms of Neutrophil Release from the Bone Marrow." Blood 122, no. 21 (November 15, 2013): SCI—43—SCI—43. http://dx.doi.org/10.1182/blood.v122.21.sci-43.sci-43.
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Abstract Neutrophils are an essential component of the innate immune response and a major contributor to inflammation. Consequently, neutrophil homeostasis in the blood is tightly regulated. This is achieved by balancing neutrophil production and release from the bone marrow with clearance of senescent neutrophils from the circulation. Here, we highlight recent studies elucidating the signals that regulate neutrophil homeostasis. Constitutive chemokine expression by bone marrow stromal cells plays a key role in regulating neutrophil egress. Specifically, CXCL12 from CXCL12-abundant reticular (CAR) cells and possibly endothelial cells serves to retain neutrophils in the bone marrow. Conversely, CXCL1/2 expression from endothelial cells may promote neutrophil egress. Consistent with these observations, gain-of-function mutations of CXCR4 (the major receptor for CXCL12) or loss-of-function mutations of CXCR2 (the major receptor for CXCL1/2) are associated with myelokathexis in humans. G-CSF promotes neutrophil release from the bone marrow, in large part, by decreasing CXCL12 expression in bone marrow stromal cells, while increasing CXCL2 expression in bone marrow endothelial cells. CXCL12 production from bone marrow stromal cells may be a target of a feedback loop involving the clearance of senescent neutrophils. Specifically, macrophage engulfment of senescent neutrophils in the bone marrow attenuates CXCL12 expression, thereby facilitating neutrophil egress. Recent data suggest that signals from gut microbiota may play a significant role in regulating neutrophil homeostasis. In particular, mice raised under germ-free conditions display marked neutropenia. Gut microbiota appear to regulate neutrophil homeostasis, at least in part through toll-like receptor signaling. These data suggest new pathways that might be targeted therapeutically to modulate neutrophil number in the blood. Disclosures: No relevant conflicts of interest to declare.
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Kish, Danielle, and Robert Fairchild. "Expression of CCL20 in hapten challenged skin induces recruitment of hapten-primed CD8 T cells producing IL-17 into the skin (CAM1P.229)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 47.5. http://dx.doi.org/10.4049/jimmunol.192.supp.47.5.
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Abstract Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to skin sensitization and challenge with hapten. Hapten-presenting endothelial cell (EC) activate hapten-primed CD8 T cells to produce IFN-γ and IL-17 in the challenge site. These cytokines stimulate the EC to produce CXCL1 and CXCL2 that direct required CXCR2+ leukocyte recruitment into the skin challenge site for elicitation of CHS. This study investigated mechanisms directing hapten-primed CD8 cell localization to the hapten presenting EC in the challenge site. In the draining lymph nodes of hapten sensitized mice, CD8 T cells expressing CCR6 produce IL-17 in response to hapten-presenting cells and CD8 T cells expressing CXCR3 produce IFN-γ. Hapten skin challenge induces CXCL9/10 and CCL20 expression within 1 h and hapten labeling of EC cultures induces CXCL9/10 and CCL20. Anti-CCL20 antibody given at the time sensitized mice are challenged with hapten reduces IL-17 and CXCL1, but not IFN-γ, expression in the skin challenge site. IL-17 and CXCL1, but not IFN-γ, expression is also reduced in the skin challenge site of sensitized TLR4-/- mice, that have low CHS responses despite wild-type levels of hapten-reactive IFN-γ and IL-17 producing CD8 T cells in the skin draining lymph nodes. These results suggest that TLR4 activation of hapten-presenting EC is required to induce the CCL20 expression directing hapten-primed CCR6+ CD8 T cells to the challenged skin site to mediate CXCL1 production and elicit CHS.
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Stock, Angus T., Jeffrey M. Smith, and Francis R. Carbone. "Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection." Journal of Experimental Medicine 211, no. 5 (April 21, 2014): 751–59. http://dx.doi.org/10.1084/jem.20132183.
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Infection induces the expression of inflammatory chemokines that recruit immune cells to the site of inflammation. Whereas tissues such as the intestine and skin express unique chemokines during homeostasis, whether different tissues express distinct chemokine profiles during inflammation remains unclear. With this in mind, we performed a comprehensive screen of the chemokines expressed by two tissues (skin and sensory ganglia) infected with a common viral pathogen (herpes simplex virus type 1). After infection, the skin and ganglia showed marked differences in their expression of the family of Cxcr2 chemokine ligands. Specifically, Cxcl1/2/3, which in turn controlled neutrophil recruitment, was up-regulated in the skin but absent from the ganglia. Within the ganglia, Cxcl2 expression and subsequent neutrophil recruitment was inhibited by type I interferon (IFN). Using a combination of bone marrow chimeras and intracellular chemokine staining, we show that type I IFN acted by directly suppressing Cxcl2 expression by monocytes, abrogating their ability to recruit neutrophils to the ganglia. Overall, our findings describe a novel role for IFN in the direct, and selective, inhibition of Cxcr2 chemokine ligands, which results in the inhibition of neutrophil recruitment to neuronal tissue.
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Boro, Monoranjan, and Kithiganahalli Narayanaswamy Balaji. "CXCL1 and CXCL2 Regulate NLRP3 Inflammasome Activation via G-Protein–Coupled Receptor CXCR2." Journal of Immunology 199, no. 5 (July 24, 2017): 1660–71. http://dx.doi.org/10.4049/jimmunol.1700129.
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Smith, David F., Elena Galkina, Klaus Ley, and Yuqing Huo. "GRO family chemokines are specialized for monocyte arrest from flow." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 5 (November 2005): H1976—H1984. http://dx.doi.org/10.1152/ajpheart.00153.2005.
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Chemokines participate in various processes of monocyte recruitment including monocyte arrest and migration. Our group and others have demonstrated that growth-related oncogene (GRO)-α (CXCL1) can support monocyte arrest in models of inflammation. Here we employed a parallel plate-flow chamber and Transwell reconstitution assay to test whether GRO family chemokines were sufficient for Mono Mac 6 (a human monocytic cell line) and isolated human monocyte recruitment. Our study shows that 1) GRO-α, -β (CXCL2), and -γ (CXCL3) all act as arrest chemokines for monocyte adhesion on vascular cell adhesion molecule (VCAM)-1 under flow in the presence of P-selectin; 2) CXCR2 is the functional receptor for GRO-family chemokines in monocyte arrest; however, CXCR2 is not an arrest chemokine receptor in general, since epithelial neutrophil-activating peptide ENA-78 failed to arrest monocytes; 3) GRO-α, -β, and -γ all fail to increase intracellular free Ca2+ or mediate monocyte chemotaxis; and 4) signaling through Gαi protein, phosphoinositide 3-kinase, and actin polymerization but not Ca2+ mobilization or the mitogen-activated kinases p38 and MAPK/extracellular signal-related kinase are necessary for GRO-α-mediated Mono Mac 6 cell arrest under flow. We conclude that the GRO-family chemokines are specialized monocyte-arrest chemokines. Their role in monocyte recruitment in inflammation can be inhibited by blocking CXCR2 function or downstream signaling events.
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Fischer, Jeffrey, Jeffrey West, Nnenaya Agochukwu, Colby Suire, and Hollie Hale-Donze. "Induction of Host Chemotactic Response by Encephalitozoon spp." Infection and Immunity 75, no. 4 (December 18, 2006): 1619–25. http://dx.doi.org/10.1128/iai.01535-06.
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ABSTRACT Microsporidians are a group of emerging pathogens typically associated with chronic diarrhea in immunocompromised individuals. The number of reports of infections with these organisms and the disseminated pathology is growing as diagnostic tools become more readily available. However, little is known about the innate immune response induced by and generated against these parasites. Using a coculture chemotaxis system, primary human macrophages were infected with Encephalitozoon cuniculi or Encephalitozoon intestinalis, and the recruitment of naïve monocytes was monitored. Encephalitozoon spp. induced an average threefold increase in migration of naïve cells 48 h postinfection, which corresponded to optimal infection of monocyte-derived-macrophages. A limited microarray analysis of infected macrophages revealed several chemokines involved in the inflammatory responses whose expression was upregulated, including CCL1, CCL2, CCL3, CCL4, CCL7, CCL15, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8. The levels of 6 of 11 chemokines also present in the microarray were confirmed to be elevated by protein profiling. Kinetic studies confirmed that secreted CCL2, CCL3, and CCL4 were expressed as early as 6 h postinfection, with peak expression at 12 to 24 h and expression remaining until 48 h postinfection. Neutralization of these chemokines, specifically CCL4, significantly reduced the number of migrating cells in vitro, indicating their role in the induction of monocyte migration. This mechanism of recruitment not only supports the evidence that in vivo cellular infiltration occurs but also provides new hosts for the parasites, which escape macrophages by rupturing the host cell. To our knowledge, this is the first documentation that chemokine production is induced by microsporidian infections in human macrophages.