Articles de revues sur le sujet « CXCL12/CXCR4 axi »

Background/Aims: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI.

The acute lung injury (ALI) causes severe pulmonary diseases, leading to a high mortality rate. The Renshen and Chishao have protective and anti-inflammatory effects against the ALI. To explore the protective effects of the Renshen Chishao (RC) decoction against the ALI, we established the lipopolysaccharide-indued ALI model and randomly divided the mice into seven groups: control group, ALI group, high-dose RC group, middle-dose RC group, low-dose RC group, middle-dose RC group + CXCR2 antagonist group, and ALI + CXCR2 antagonist group. We estimated the lung injury by the hematoxylin and eosin staining, the neutrophil extracellular traps (NETs) formations by the immunofluorescence colocalization and enzyme-linked immunosorbent assay (ELISA), and the CXCR2/CXCL2 pathway by the flow cytometry, ELISA, and real-time polymerase chain reaction. We conducted the high-throughput sequencing and enrichment analyses to explore the potential mechanisms. The results showed that the RC decoction pathologically ameliorated the lipopolysaccharide-induced lung injury and inflammatory response but failed to reduce the circulating and lung tissue NETs formation and the blood neutrophil percent. The high-dose RC decoction increased the plasma CXCL2 level, but the RC decoction had no effects on the neutrophilic CXCR2 levels. Under the inhibition of the CXCR2, the middle-dose RC decoction still decreased the lung injury score but as yet had unobvious influence on the NETs formation. Other potential mechanisms of the RC decoction against the ALI involved the pathways of ribosome and coronavirus disease 2019 (COVID-19); the target genes of inflammatory factors, such as Ccl17, Cxcl17, Cd163, Cxcr5, and Il31ra, and lncRNAs; and the regulations of the respiratory cilia. In conclusion, the RC decoction pathologically ameliorated the lipopolysaccharide-induced lung inflammatory injury via upregulating the CXCL2/CXCR2 pathway but could not reduce the circulating or lung tissue NETs formation.

Astragaloside IV (ASI) has been reported to promote neural stem cells proliferation in vitro and CXCR2 expression on neutrophils. The present study was aimed to investigate the influence of ASI on adult neurogenesis in hippocampal dentate gyrus (DGs) of mouse and to discuss the possible underlying mechanisms. Total number of proliferative cells (BrdU+), pre-mature neurons (DCX+), early proliferative cells (BrdU+/DCX+), proliferative radial gila-like cells (BrdU+/GFAP+) and newly generated neurons (BrdU+/NeuN+) after ASI or vehicle administration for two weeks were counted, respectively. The results showed that BrdU+ cells and DCX+ cells were significantly increased in DGs of mice administered with ASI. The numbers of BrdU+/DCX+, BrdU+/GFAP+ cells and BrdU+/NeuN+ cells were also elevated in the ASI group. Correspondingly, ASI increased the protein expression of hippocampal DCX, GFAP and NeuN. Further study disclosed that ASI remarkably up-regulated the mRNA and protein expressions of CXCL1 as well as that of CXCR2 in the hippocampus. The promotive effect of ASI on DCX, GFAP and NeuN protein expression was abolished by SB225002, the inhibitor of CXCR2. Our results indicated that ASI modulated the homeostasis of the CXCL1/CXCR2 signaling pathway, which might be responsible for the increased neurogenesis within the hippocampal DGs of mice.

Serum IL-6 is increased in patients with acute kidney injury (AKI) and is associated with prolonged mechanical ventilation and increased mortality. Inhibition of IL-6 in mice with AKI reduces lung injury associated with a reduction in the chemokine CXCL1 and lung neutrophils. Whether circulating IL-6 or locally produced lung IL-6 mediates lung injury after AKI is unknown. We hypothesized that circulating IL-6 mediates lung injury after AKI by increasing lung endothelial CXCL1 production and subsequent neutrophil infiltration. To test the role of circulating IL-6 in AKI-mediated lung injury, recombinant murine IL-6 was administered to IL-6-deficient mice. To test the role of CXCL1 in AKI-mediated lung injury, CXCL1 was inhibited by use of CXCR2-deficient mice and anti-CXCL1 antibodies in mice with ischemic AKI or bilateral nephrectomy. Injection of recombinant IL-6 to IL-6-deficient mice with AKI increased lung CXCL1 and lung neutrophils. Lung endothelial CXCL1 was increased after AKI. CXCR2-deficient and CXCL1 antibody-treated mice with ischemic AKI or bilateral nephrectomy had reduced lung neutrophil content. In summary, we demonstrate for the first time that circulating IL-6 is a mediator of lung inflammation and injury after AKI. Since serum IL-6 is increased in patients with either AKI or acute lung injury and predicts prolonged mechanical ventilation and increased mortality in both conditions, our data suggest that serum IL-6 is not simply a biomarker of poor outcomes but a pathogenic mediator of lung injury.

We examined whether antagonism of the CXCR4 receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR4 is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR4 antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR4 inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR4 antagonism with plerixafor may be a potential option to prevent AKI.

Background/Aims: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are lethal diseases in humans, and the current treatments have limited therapeutic effects. Cordyceps militaris (CM) is a caterpillar-grown traditional medicinal mushroom, and has been used as a natural invigorant for longevity, endurance, and vitality in China. Recently, purified extracts from CM have been shown to have beneficial effects on various diseases including cancer. Nevertheless, a role of CM in ALI has not been examined previously. Methods: Here, we used a bleomycin-induced ALI model to study the effects of CM on the severity of ALI in mice. The levels of CXCR2, a receptor for Interleukin 8 (IL-8) in pulmonary microvascular endothelial cells, were examined in different experimental groups. The levels of microRNA (miR)-1321 and miR-3188 were also examined in lung samples and in CM. Adeno-associated viruses carrying miR-1321 and miR-3188 were injected into bleomycin-treated mice for evaluation their effects on the severity of ALI. Results: CM treatment significantly alleviated the severity of bleomycin-induced ALI in mice. The increases in lung CXCR2 by bleomycin were significantly reduced by CM at protein level, but not at mRNA level. CM contained high levels of 2 miRNAs (miR-1321 and miR-3188) that target 3'-UTR of CXCR2 mRNA to inhibit its expression. Overexpression of miR-1321 and miR-3188 in mouse lung through AAV-mediated gene therapy mimicked the effects of CM. Conclusion: CM may alleviate severity of murine ALI through miRNAs-mediated CXCR2 inhibition.

Abstract CCL2-CCR2 signaling plays an essential role in the recruitment of macrophages and neutrophils following tissue injury. During inflammation, CCR2+ macrophage secretion of CCL2 induces an autocrine effect that leads to an intracellular signaling cascade of macrophages that promotes upregulation of CCL2, CXCL2, and CXCL3 expression, which stimulates the chemotaxis of blood circulating CCR2+ monocytes and CXCR2+ neutrophils to the disease site. Interestingly, the aryl hydrocarbon receptor (AhR) ligand has been shown to regulate effector cell recruitment. Therefore, we studied the effects of the AhR ligand, indole-3-carbinol (I3C) on the recruitment of circulating CCR2+ monocytes and CXCR2+ neutrophils during acute lung injury (ALI). To induce ALI in C57BL/6 mice and Ccr2gfp mice (mice deficient in the CCR2 receptor), they were given 5mg/kg of lipopolysaccharide intranasally. Mice were treated with I3C or vehicle following disease induction. Interestingly, I3C downregulated neutrophils expressing CXCR2 (a receptor associated with neutrophil recruitment) and CCR2+ macrophages in lungs of C57BL/6 diseased-mice. Furthermore, to determine if CCR2+ macrophages recruit CXCR2+ neutrophils, we induced ALI in Ccr2gfp mice. Abolishing the expression of CCR2 eliminated the recruitment of CXCR2+ neutrophils to the lungs during ALI. Interestingly, scRNASeq of macrophage/monocyte cells showed that I3C reduced expression of CXCL3. CXCL3 gene translates into the chemokine CXCL3, which binds to CXCR2 and is involved in neutrophil recruitment to the disease site. These findings suggest that CCR2 macrophages are involved in the recruitment of CXCR2+ neutrophils, and the AhR ligand I3C can regulate immune cell trafficking capabilities. Supported by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788, R01AI123947, R01AI160896 and R01AI123947-S2

The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsis-induced acute lung injury (ALI) remains unclear. Lipopolysaccharide (LPS), also known as endotoxin, has been used to induce ALI. The goal of this study was to assess the effect of nintedanib in attenuating the histopathological changes of LPS-induced ALI. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h and 10 min before intratracheal endotoxin instillation. Lung histopathological characteristics, adhesion molecule expression, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed after 24 h. We found that nintedanib significantly reduced histopathological changes and neutrophil recruitment in LPS-induced ALI. The number of neutrophils in bronchoalveolar lavage fluid (BALF) was reduced in nintedanib-treated relative to untreated mice with ALI. Nintedanib mediated the downregulation of the chemotactic response to LPS by reducing the expression of adhesion molecules and the phosphorylated p38:total p38 mitogen-activated protein kinase (MAPK) ratio in the lungs of mice with ALI. Nintedanib also reduced the expression of lymphocyte antigen 6 complex locus G6D (Ly6G) and very late antigen 4 (VLA-4) in BALF neutrophils and mediated the downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in mice with LPS-induced ALI. Nintedanib improved the histopathological changes of LPS-induced ALI by reducing neutrophil chemotaxis. These effects were mediated by the inhibition of adhesion molecules via the activation of GRK2 and the inhibition of p38 MAPK and CXCR2.

AbstractBackgroundCisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI.MethodsIn in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay.ResultsIn in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG.ConclusionsThe DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.

Abstract The BM contains progenitor cells that give rise to hematopoietic tissue and also more primitive mesenchymal stem cells (MSC) which may differentiate into other tissues including endothelial cells. This potential of BM cells has already been employed in clinical studies suggesting that implantation of autologous BM cells may induce angiogenesis in ischemic tissues. In the present study 10 male pts with critical leg ischemia (41–64 yrs) suffering from pain at rest and/or foot ischemic ulceration (9/10 pts) with ABI (ankle/brachial index) <0.5 in 8/10 pts in whom surgical treatments were exhausted were enrolled in this study. 0.5L of BM obtained from the iliac posterior crest were processed in a Cobe Spectra 6.0 separator to remove RBC and to reduce the number of granulocytes. Fresh BM populations and those after processing were evaluated for phenotype characteristics and for the presence of transcripts for VEGF and for SDF1-CXCR4, CX3CL-CXCR1 gene pair expression. Usually 40 ml of cell suspensions were injected in 0.5 ml portions to ischemic muscles and the fate of the pts was evaluated in an out-pts observation setting for 5–7 mths. The number of WBC implanted was (mean±SEM) 30.2x108±4.5 which contained the following percentages of subpopulations CD34+ 1.58±0.25, CD45−CD34− 10.8±0.96, CD45−CD34−CD90+ 0.1±0.02, CD45−CD34−CD105+ 2.8±0.4, CD45−CD34−CD73+ 0.07±0.01 and 24 CFU-F/106 WBC. The positive effect of implantation was seen 2 days after the procedure with substantial pain reduction from 6.17±0.35 to 4.63±1.03 (p=0.04) 10 days and to 3.66±1.35 3 mths after implantation (p=0.034). ABI improved from 0.47±0.07 before to 0.66±0.06 (p=0.02) 10 days and to 0.66±0.07 (p=0.02) 3 mths after. This improvement was followed by ulceration healing in 5/9 pts (area of ulceration prior to implantation was 502.3±269.2 mm2 and 2 mths after was 32.3±23.6 mm2) in 2 pts ulceration healed completely. In 10 cases arteriography performed 3 mths after implantation documented new arteriole formation in 6 pts. The positive effect may not be long lasting in all pts as in 3/10 pts the pain at rest recurred and in 2 pts ulceration progressed 2 mths after implantation. The positive effect of the treatment could not be attributed to any of the described cell populations separately as evaluated by correlation analysis. In this study we identified cells with MSC characteristics in the BM population that were further enriched in MNC and implanted to ischemic muscles. In fresh BM cell populations and those after cell processing, the transcripts for VEGF and SDF1-CXCR4 and CXCL3-CXCR1 pairs were found. Implantation of these cells resulted in early, intermediate and late effects with pain relief, ischemic ulceration healing and finally arteriole length density, respectively. The pace of improvement suggested that the processed BM population while injected to ischemic muscles may act via cyto-/chemokine release with an analgetic effect and local immunity improvement. Furthermore, ulceration healing seen 10 days after implantation followed by neovascularization is likely due to auto/paracrine effects within a population of MSC that express genes facilitating the homing of vascular progenitors and play a role in new vessels formation. Supp by the grant PBZ-KBN-083/P05/2002 from the Polish State Committee Sci. Res.

Abstract Prostate cancer is the most common cancer among men. Currently, targeting the AR pathway, chemotherapy or immune-based therapies are major options but only provide a modest improvement in overall survival. RNA binding proteins have been shown to regulate AR expression in the progression of PCa. We and others have demonstrated that RNA binding protein RBM3 is upregulated in various solid tumors including PCa. We have also shown that RBM3 binds to 3’UTR of mRNAs of tumor-promoting factors and increases their mRNA stability and translation. However, the role of RBM3 in PCa is not well evaluated. We first analyzed the expression levels of RBM3 in the TCGA database. There was a significant increase in RBM3 expression even in cancers with a Gleason score of 6 upto Gleason 10 cancers. To confirm this we performed RT-PCR analyses of a prostate cancer cDNA panel. There was a significant increase in RBM3 expression in the PCa tissues compared to normal control. We used LNCaP and its derivative cell line C4-2B which show features of progressed disease such as metastatic capability and hormone independence. RT-PCR and western blot analyses demonstrated significantly higher RBM3 levels in C4-2B cells as compared to LNCaP cells suggesting a role for RBM3 in tumor progression. The tumor microenvironment also plays a very important role in prognosis of PCa. Specifically, tumor-associated macrophages (TAMs) have been shown to increase metastatic potential and increase tumor angiogenesis. To determine the levels of RBM3 expression and its effects on macrophage infiltration, we mined the TCGA database using TIMER2.0 software. There was a positive correlation of RBM3 expression with infiltration of both M1 and M2 macrophages. To further study the effect of interactions between PCa cells and TAMs, we used immortalized THP1 monocytes, which can be activated to M1 and M2 macrophages. We observed that just converting the THP1 cells to M1 or M2 macrophages increased RBM3 expression in both cell types. Also, when M1 and M2 macrophages were treated with conditioned media from LNCaP or C4-2B cells, there was an induction in the expression of RBM3. Similarly, when conditioned media from M0, M1, M2 activated THP1 cells were applied to LNCaP and C4-2B cells, there was an increase in RBM3 expression in the PCa cells. This suggests a positive cross-talk between the macrophages and PCa cells. We evaluated the cytokine profile in the conditioned media from M1 and M2 macrophages and determined that while M1 macrophages had increased levels of CXCL10, M2 macrophages showed higher levels of IL4 and IL10. Moreover, PCa cells have higher levels of CXCR3, the receptor for CXCL10. Together, these data suggest that crosstalk between TAMs and cancer cells in the PCA microenvironment plays a significant role in increasing RBM3 expression, which in turn enhances global translation of disease progression related genes. Citation Format: Afreen Asif Ali Sayed, David Standing, Prasad Dandawate, Shahid Umar, Roy Jensen, Rahul Parikh, John Taylor, Shrikant Anant. Determining the expression of RNA binding protein Rbm3 in tumor cells and immune cells in the tumor microenvironment in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2558.

Abstract Background: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by expansion of clonal IgM-secreting cells (Advani P, et al. Hematol Oncol Stem Cell Ther. 2019;12:179-188). While ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) currently approved by the US FDA and EMA for WM, other BTKi's are currently under investigation. More than 90% of patients with WM have somatic mutations in MYD88, and 30%-40% of these patients have activating mutations in CXCR4WHIM (Xu L, et al. Br J Haematol. 2016;172:735-744; Treon SP, et al. Blood. 2014;123:2791-2796). CXCR4WHIM in WM is associated with high serum IgM level, symptomatic hyperviscosity, earlier time to treatment, and inferior response to approved and investigational BTKi (Schmidt J, et al. Br J Haematol. 2015;169:795-803;Tam C, et al. Blood. 2020; 136:2038-2050). Inhibition of CXCR4 can sensitize CXCR4WHIM-expressing cells to ibrutinib (Cao Y, et al. Leukemia. 2015;29:169-176). Mavorixafor is an oral small-molecule antagonist of CXCR4. In vitro data have shown that mavorixafor inhibits CXCL12 binding and extracellular signal regulated kinase hyperactivation for CXCR4 mutations. Aims: To report on an early assessment of the safety and clinical response of mavorixafor in combination with ibrutinib after ≥6 months (6 cycles) of treatment in patients with MYD88 and CXCR4WHIM WM. Methods: This is an ongoing phase 1b, open-label, multicenter, single-arm study (NCT04274738) examining intrapatient dose escalation, safety, pharmacokinetics (PK), and pharmacodynamics of mavorixafor in combination with ibrutinib (target N=18). Eligibility includes age ≥18 years, clinicopathological WM diagnosis, consensus criteria indication for treatment, measurable disease, 0-3 prior therapies, and confirmed MYD88 and CXCR4WHIM mutations. Patients are initiated on mavorixafor 200 mg (low-dose) and ibrutinib 420 mg, both oral and once-daily. Mavorixafor escalation to 400 mg (mid-dose) occurs after 28 days if no dose-limiting toxicities (DLTs) are observed and to 600 mg (high-dose) after 400 mg is deemed safe (&lt;2/6 DLTs). Patients are followed for adverse events (AEs), and change from baseline in IgM, Hgb, PK, WBC counts, and clinical responses. Results: At data cutoff of June 15, 2021, 10 patients have enrolled, with 9 dosed and 9 continuing on study. Both 200-mg and 400-mg mavorixafor doses in combination with ibrutinib were deemed safe. Dosing at 600 mg is ongoing. Median duration of treatment was 198 days. A total of 107 AEs were observed (79% grade 1). Of 92 AEs with complete assessment for causal relationship to study drugs, 9 were deemed related to mavorixafor only, 13 to ibrutinib only, and 18 to the combination. One DLT was observed, consisting of grade 3 hypertension attributed to combination therapy. Two grade 2 AEs attributed to mavorixafor only led to drug interruption (7-8 days). Overall response rate for evaluable patients (minor response or better) was 100% (N=8). Four of 8 patients achieved major response; 1 of 8 patients achieved very good partial response. All 9 patients showed decrease in serum IgM while on treatment, with IgM levels normalizing in 1 patient after 4 months' treatment. For all patients treated for ≥6 months (N=7), median absolute serum IgM level decreased to 31.04 g/L at 6 months from pretreatment level of 46.23 g/L . Mean Hgb increased by &gt;20 g/L, with Hgb approaching normal levels in these 7 patients. Mavorixafor and ibrutinib exposures were consistent with previous reports (de Jong J, et al. Cancer Chemother Pharmacol. 2015;75(5):907-916), and combination treatment increased peripheral lymphocytes, neutrophils, and monocytes in all 9 patients. Conclusion: Our findings as of June 2021 in patients with WM carrying both MYD88 and CXCR4WHIM mutations show that mavorixafor in combination with ibrutinib is well tolerated. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug-drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. All evaluable patients demonstrated at least a minor response. Combination of mavorixafor with ibrutinib led to rapid, clinically meaningful, and durable decrease in IgM levels and increase in Hgb levels. These ongoing studies support the feasibility of combining ibrutinib with mavorixafor to improve responses in MYD88 CXCR4WHIM WM. Disclosures Treon: BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; Pharmacyclics: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; X4: Research Funding. Buske: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding. Thomas: Genentech: Research Funding; X4 Pharma: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Branagan: CSL Behring: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Gavriatopoulou: Genesis: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; GSK: Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garzon: X4 Pharmaceuticals: Consultancy. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Seyffert: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ali: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.

Inflammation that develops with the release of chemokines and cytokines during acute kidney injury (AKI) has been shown to participate in functional renal recovery. While a major research focus has been on the role of macrophages, the family of CXC motif chemokines that promote neutrophil adherence and activation also increase with kidney ischemia/reperfusion (I/R) injury. This study tested the hypothesis that intravenous delivery of endothelial cells that overexpress CXCR1 and CXCR2 improves outcomes in kidney I/R injury. Overexpressing CXCR1/2 enhanced homing of ECs to I/R-injured kidneys and limited interstitial fibrosis, capillary rarefaction and tissue injury biomarkers (serum creatinine concentration and urinary KIM-1) following AKI and also reduced expression of P-selectin, the rodent CXC motif chemokine, CINC-2β, and the number of MPO-positive cells in the post-ischemic kidney. The serum chemokine/cytokine profile, including CINC-1, showed similar reductions. These findings were not observed in rats given endothelial cells transduced with empty adenoviral vector (Null-EC) or vehicle alone. These data indicate that extrarenal endothelial cells that overexpress CXCR1 and CXCR2, but not Null-EC or vehicle alone, reduce I/R kidney injury and preserve kidney function in a rat model of AKI.