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Mice deficient in the CXCR2 ligand, CXCL1 (KC/GRO-), exhibit increased susceptibility to dextran sodium sulfate (DSS)-induced colitis

Department of Medicine, University of Maryland, Mucosal Biology Research Center, University of Maryland

Karen Thomas

Department of Microbiology and Immunology, University of Maryland

M. Joshua Cody

Department of Microbiology and Immunology, University of Maryland

Aiping Zhao

Department of Medicine, University of Maryland, Mucosal Biology Research Center, University of Maryland

Louis J. DeTolla

Department of Medicine, University of Maryland, Program of Comparative Medicine, Department of Pathology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA

Karen M. Kopydlowski

Pharmaceutical Systems Division, United States Army, Medical Materiel Development Activity, Fort Detrick, Maryland, USA

Masayuki Fukata

Immunobiology Institute, Mount Sinai School of Medicine, New York, USA

Sergio A. Lira

Immunobiology Institute, Mount Sinai School of Medicine, New York, USA

Stefanie N. Vogel

Department of Microbiology and Immunology, University of Maryland, Program of Comparative Medicine, Department of Pathology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA, svogel{at}som.umaryland.edu

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.

Key Words: CXCL1/KC • dextran sodium sulfate • colitis

Innate Immunity, Vol. 14, No. 2, 117-124 (2008)
DOI: 10.1177/1753425908088724


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