Inhibition of CXCR4 and CXCR7 Is Protective in Acute Peritoneal Inflammation

Ngamsri, Kristian-Christos; Jans, Christoph; Putri, None Rizki A; Schindler, Katharina; Gamper-Tsigaras, Jutta; Eggstein, Claudia; Köhler, David; Konrad, Franziska M.

doi:10.3389/fimmu.2020.00407

Cited by 23 publications

(18 citation statements)

References 76 publications

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“…In addition, unlike CCR5, which interacts with several types of ligands, CXCR4 has an exclusive ligand known as SDF-1. As reported, the interaction between CXCR4 and SDF-1 mainly regulates the generation, transport, homing and retention of CXCR4-positive blood cells in hematopoietic organs and the accumulation of CXCR4-positive immune cells in inflammatory sites (34)(35)(36)(37)(38). Previous studies have shown that SDF-1 correlated with HIV infection, cardiovascular disease and the mobilization of hematopoietic stem and progenitor cells (39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 79%

γδ T Cells May Aggravate Acute Graft-Versus-Host Disease Through CXCR4 Signaling After Allogeneic Hematopoietic Transplantation

Liu

Liang

et al. 2021

Front. Immunol.

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Graft-versus-host disease (GVHD) is a pathology in which chemokines and their receptors play essential roles in directing the migration of alloreactive donor T cells into GVHD organs, thereby leading to further target tissue damage. Currently, acute GVHD (aGVHD) remains a major cause of high morbidity and mortality in patients who underwent allogeneic hematopoietic cell transplantation (alloHCT). The identification of immune cells that correlate with aGVHD is important and intriguing. To date, the involvement of innate-like γδ T cells in the pathogenesis of aGVHD is unclear. Herein, we found that primary human γδ T cells did not directly trigger allogeneic reactions. Instead, we revealed that γδ T cells facilitated the migration of CD4 T cells via the SDF-1-CXCR4 axis. These results indicate indirect regulation of γδ T cells in the development of aGVHD rather than a direct mechanism. Furthermore, we showed that the expression of CXCR4 was significantly elevated in γδ T cells and CD4 and CD8 T cells in recipients who experienced grades II-IV aGVHD after alloHCT. Consistently, CXCR4-expressing γδ T cells and CD4 T cells were induced in the target organs of mice suffering aGVHD. The depletion of γδ T cells in transplant grafts and treatment with AMD3100, an inhibitor of CXCR4 signaling, delayed the onset of aGVHD and prolonged survival in mice. Taken together, these findings suggest a role for γδ T cells in recruiting alloreactive CD4 T cells to target tissues through the expression of CXCR4. Our findings may help in understanding the mechanism of aGVHD and provide novel therapeutic targets.

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Section: Discussionmentioning

confidence: 79%

γδ T Cells May Aggravate Acute Graft-Versus-Host Disease Through CXCR4 Signaling After Allogeneic Hematopoietic Transplantation

Liu

Liang

et al. 2021

Front. Immunol.

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“…Because the protective effects of the anesthetic were greatest 1 h after zymosan installation, we chose this time point for all subsequent experiments, including fecal-induced peritonitis experiments as described previously. 17…”

Section: Peritonitis Models and Applicationmentioning

confidence: 99%

“…With a Vectastain ABC kit, neutrophil accumulation in the intestine, lung, and liver tissue was visualized by immunohistochemistry (Vector Laboratories, Germany) as previously described. 17 Tissue slides were processed with a Leitz DM IRB microscope (Leica, Germany) and analyzed with AxioVision, version 4.8.2 (Carl Zeiss, Germany).…”

Section: Immunohistochemical Neutrophil Detectionmentioning

confidence: 99%

Sevoflurane Exerts Protective Effects in Murine Peritonitis-induced Sepsis via Hypoxia-inducible Factor 1α/Adenosine A2B Receptor Signaling

Ngamsri¹,

Fabian²,

Fuhr³

et al. 2021

Anesthesiology

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Background Sepsis is one of the leading causes of mortality in intensive care units, and sedation in the intensive care unit during sepsis is usually performed intravenously. The inhalative anesthetic sevoflurane has been shown to elicit protective effects in various inflammatory studies, but its role in peritonitis-induced sepsis remains elusive. The hypothesis was that sevoflurane controls the neutrophil infiltration by stabilization of hypoxia-inducible factor 1α and elevated adenosine A2B receptor expression. Methods In mouse models of zymosan- and fecal-induced peritonitis, male mice were anesthetized with sevoflurane (2 volume percent, 30 min) after the onset of inflammation. Control animals received the solvent saline. The neutrophil counts and adhesion molecules on neutrophils in the peritoneal lavage of wild-type, adenosine A2B receptor −/−, and chimeric animals were determined by flow cytometry 4 h after stimulation. Cytokines and protein release were determined in the lavage. Further, the adenosine A2B receptor and its transcription factor hypoxia-inducible factor 1α were evaluated by real-time polymerase chain reaction and Western blot analysis 4 h after stimulation. Results Sevoflurane reduced the neutrophil counts in the peritoneal lavage (mean ± SD, 25 ± 17 × 105vs. 12 ± 7 × 105 neutrophils; P = 0.004; n = 19/17) by lower expression of various adhesion molecules on neutrophils of wild-type animals but not of adenosine A2B receptor −/− animals. The cytokines concentration (means ± SD, tumor necrosis factor α [pg/ml], 523 ± 227 vs. 281 ± 101; P = 0.002; n = 9/9) and protein extravasation (mean ± SD [mg/ml], 1.4 ± 0.3 vs. 0.8 ± 0.4; P = 0.002; n = 12/11) were also lower after sevoflurane only in the wild-type mice. Chimeric mice showed the required expression of the adenosine A2B receptor on the hematopoietic and nonhematopoietic compartments for the protective effects of the anesthetic. Sevoflurane induced the expression of hypoxia-inducible factor 1α and adenosine A2B receptor in the intestine, liver, and lung. Conclusions Sevoflurane exerts various protective effects in two murine peritonitis-induced sepsis models. These protective effects were linked with a functional adenosine A2B receptor. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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“…Although PMs did not express detectable cell surface levels of CXCR4, they did respond to stimulations of CXCL12, and its expression increased during acute inflammatory peritonitis ( 48 , 49 ). The increased expression of CXCR4 in macrophages under inflammation stimuli explained the increased amount of CD68+ macrophages after modeling and increased proportions of PMs at the 10 and 18 th weeks when the intestinal inflammation response aggravated alongside CRC development.…”

Section: Discussionmentioning

confidence: 94%

Functional Phenotypes of Peritoneal Macrophages Upon AMD3100 Treatment During Colitis-Associated Tumorigenesis

Luo

et al. 2022

Front. Med.

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CXCL12 and its receptor CXCR4 are independent prognostic factors in colorectal cancer. AMD3100 is the most frequently used FDA-approved antagonist that targets the CXCL12-CXCR4 axis in clinical trials. We aimed to explore the role of AMD3100 and its effect on peritoneal macrophages' functional phenotypes during colitis-associated tumorigenesis. We treated AMD3100 in a colitis-associated colon cancer mouse model and evaluated its effect on tumorigenesis. The phagocytosis activities of peritoneal macrophages were measured by flow cytometry. The proportions of macrophages and M1/M2 subpopulations were investigated by flow cytometry, ELISA, and immunochemistry. Serum levels of pro-inflammatory and anti-inflammatory cytokines were measured by LEGENDplex™ kits. Transwell assay and qRT-PCR were performed to investigate the direct effect of CXCL12 on macrophages in vitro. We demonstrated that AMD3100 treatment reduced the inflammatory damages in the colonic mucosal and ameliorated tumor development in experimental mice. We found that the phagocytosis activities of peritoneal macrophages fluctuated during colitis-associated tumorigenesis. The proportions of peritoneal macrophages and M1/M2 subpopulations, together with their metabolite and cytokines, changed dynamically in the process. Moreover, AMD3100 regulated the functional phenotypes of macrophages, including reducing the recruiting activity, promoting polarization to the M1 subpopulation, and reducing IL-12 and IL-23 levels in serum. Our study contributes to understanding dynamic changes of peritoneal macrophages upon AMD3100 treatment during tumorigenesis and sheds light on the potential therapeutic target of AMD3100 and peritoneal macrophages against colitis-associated colon cancer.

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Inhibition of CXCR4 and CXCR7 Is Protective in Acute Peritoneal Inflammation

Cited by 23 publications

References 76 publications

γδ T Cells May Aggravate Acute Graft-Versus-Host Disease Through CXCR4 Signaling After Allogeneic Hematopoietic Transplantation

γδ T Cells May Aggravate Acute Graft-Versus-Host Disease Through CXCR4 Signaling After Allogeneic Hematopoietic Transplantation

Sevoflurane Exerts Protective Effects in Murine Peritonitis-induced Sepsis via Hypoxia-inducible Factor 1α/Adenosine A2B Receptor Signaling

Functional Phenotypes of Peritoneal Macrophages Upon AMD3100 Treatment During Colitis-Associated Tumorigenesis

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