Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice.
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.
Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. meij@email.chop.edu
Junjie
J
Mei
Yuhong
Y
Liu
Ning
N
Dai
Christian
C
Hoffmann
Kristin M
KM
Hudock
Peggy
P
Zhang
Susan H
SH
Guttentag
Jay K
JK
Kolls
Paula M
PM
Oliver
Frederic D
FD
Bushman
G Scott
GS
Worthen
D000818:Animals; D002469:Cell Separation; D054365:Chemokine CXCL5 / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006706:Homeostasis; D020381:Interleukin-17 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D023063:Receptors, Interleukin-8B / Q000378:metabolism*
D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D020381:Interleukin-17; D023063:Receptors, Interleukin-8B; D016179:Granulocyte Colony-Stimulating Factor