Mice deficient in the CXCR2 ligand, CXCL1 (KC/GRO-alpha), exhibit increased susceptibility to dextran sodium sulfate (DSS)-induced colitis.
The role of TLRs and MyD88 in the maintenance of gut integrity in response to dextran sodium sulfate (DSS)-induced colitis was demonstrated recently and led to the conclusion that the innate immune response to luminal commensal flora provides necessary signals that facilitate epithelial repair and permits a return to homeostasis after colonic injury. In this report, we demonstrate that a deficit in a single neutrophil chemokine, CXCL1/KC, also results in a greatly exaggerated response to DSS. Mice with a targeted mutation in the gene that encodes this chemokine responded to 2.5% DSS in their drinking water with significant weight loss, bloody stools, and a complete loss of gut integrity in the proximal and distal colon, accompanied by a predominantly mononuclear infiltrate, with few detectable neutrophils. In contrast, CXCL1/KC(- /-) and wild-type C57BL/6J mice provided water showed no signs of inflammation and, at this concentration of DSS, wild-type mice showed only minimal histopathology, but significantly more infiltrating neutrophils. This finding implies that neutrophil infiltration induced by CXCL1/KC is an essential component of the intestinal response to inflammatory stimuli as well as the ability of the intestine to restore mucosal barrier integrity.
Shea-Donohue
Terez
T
Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Thomas
Karen
K
Cody
M Joshua
MJ
Aiping Zhao
Detolla
Louis J
LJ
Kopydlowski
Karen M
KM
Fukata
Masayuki
M
Lira
Sergio A
SA
Vogel
Stefanie N
SN
D000818:Animals; D054360:Chemokine CXCL1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004198:Disease Susceptibility; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism
D054360:Chemokine CXCL1; D016264:Dextran Sulfate