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Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice
Junjie Mei, … , Frederic D. Bushman, G. Scott Worthen
Junjie Mei, … , Frederic D. Bushman, G. Scott Worthen
Published February 13, 2012
Citation Information: J Clin Invest. 2012;122(3):974-986. https://doi.org/10.1172/JCI60588.
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Research Article Immunology Article has an altmetric score of 4

Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice

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Abstract

Neutrophils are essential for maintaining innate immune surveillance under normal conditions, but also represent a major contributor to tissue damage during inflammation. Neutrophil homeostasis is therefore tightly regulated. Cxcr2 plays a critical role in neutrophil homeostasis, as Cxcr2–/– mice demonstrate mild neutrophilia and severe neutrophil hyperplasia in the bone marrow. The mechanisms underlying these phenotypes, however, are unclear. We report here that Cxcr2 on murine neutrophils inhibits the IL-17A/G-CSF axis that regulates neutrophil homeostasis. Furthermore, enterocyte-derived Cxcl5 in the gut regulates IL-17/G-CSF levels and contributes to Cxcr2-dependent neutrophil homeostasis. Conversely, G-CSF was required for Cxcl5-dependent regulation of neutrophil homeostasis, and inhibition of IL-17A reduced plasma G-CSF concentrations and marrow neutrophil numbers in both Cxcl5–/– and Cxcr2–/– mice. Cxcr2–/– mice constitutively expressed IL-17A and showed increased numbers of IL-17A–producing cells in the lung, terminal ileum, and spleen. Most IL-17–producing splenocytes were responsive to IL-1β plus IL-23 in vitro. Depletion of commensal microbes by antibiotic treatment in Cxcr2–/– mice markedly decreased IL-17A and G-CSF expression, neutrophilia, and marrow myeloid hyperplasia. These data suggest a critical role for Cxcr2, Cxcl5, and commensal bacteria in regulation of the IL-17/G-CSF axis and neutrophil homeostasis at mucosal sites and have implications for the development of treatments for pathologies resulting from either excessive or ineffective neutrophil responses.

Authors

Junjie Mei, Yuhong Liu, Ning Dai, Christian Hoffmann, Kristin M. Hudock, Peggy Zhang, Susan H. Guttentag, Jay K. Kolls, Paula M. Oliver, Frederic D. Bushman, G. Scott Worthen

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Figure 2

Cxcr2 on neutrophils inhibits G-CSF and IL-17A expression in plasma and regulates neutrophil homeostasis in the BM.

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Cxcr2 on neutrophils inhibits G-CSF and IL-17A expression in plasma and ...
(A and B) The plasma G-CSF (A) and IL-17A (B) levels in WT and Cxcr2–/– mice (n = 4 mice/group) were measured by ELISA. (C–E) The Gr-1+ cell percentages (C) from the BM of the BM-reconstituted mice (n = 4 mice/group) were determined by flow cytometry, and the plasma levels of G-CSF (D) and IL-17A (E) were measured by ELISA. WW, WT BM into WT recipient mice; WK, WT BM into Cxcr2–/– recipient mice; KW, Cxcr2–/– BM into WT recipient mice; KK, Cxcr2–/– BM into Cxcr2–/– recipient mice. Isolated BM neutrophils (107) from WT and Cxcr2–/– mice were intravenously injected into Cxcr2–/– mice (n = 3 mice/group). (F and G) After 24 hours, the plasma was prepared by coagulation-negative bleeding, and the plasma levels of G-CSF (F) and IL-17A (G) were measured by ELISA. ND, not detected. Values are means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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