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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 4

Resident cell–derived Cxcl5 is responsible for regulating neutrophil homeostasis in BM, and Cxcl5 is expressed by AE II cells in the lung and enterocytes in the ileum under basal conditions.

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Resident cell–derived Cxcl5 is responsible for regulating neutrophil hom...
(A) BM Gr-1+ cell percentages from BM-reconstituted mice (n = 4 mice/group) were determined by flow cytometry. WK, WT BM into Cxcl5–/– recipient mice; KW, Cxcl5–/– BM into WT recipient mice; KK, Cxcl5–/– BM into Cxcl5–/– recipient mice. (B and C) BALF (0.8 ml) was prepared from (B) naive WT and Cxcl5–/– mice (n = 3 mice/group) and (C) BM-reconstituted mice. Cxcl5 concentrations were measured by ELISA. (D) Lung epithelial cells were isolated from C57BL/6 mice and cultured for 24–48 hours with or without brefeldin A (added 4 hours before harvesting) and the medium and cell lysate immunoblotted for Cxcl5 expression. AEC, alveolar epithelial cell; Bfa, brefeldin A; M, molecular weight marker. (E and F) Serum concentrations of Cxcl5 (E) from BM chimeric mice (n = 3 mice/group) were measured by ELISA and the terminal ileum weighted, perfused, and homogenized in 1.4 ml saline, then Cxcl5 concentrations (F) were measured by ELISA. WT and Cxcl5–/– mice were intravenously injected with 0.25 mg brefeldin A. After 6 hours, lung and terminal ileum were perfused and fixed with formalin. (G) Lung samples immunostained for Cxcl5 and ABCA3. (H) Ileum samples immunostained for Cxcl5. White arrows indicate AE II cells. Original magnification, ×20. Values are means ± SEM. *P < 0.05; **P < 0.01.

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