Therapeutic effect of blocking CXCR2 on neutrophil recruitment and dextran sodium sulfate-induced colitis.
Dextran sodium sulfate (DSS)-induced colitis in mice is characterized by polymorphonuclear neutrophil (PMN) infiltration into the colonic mucosa and lumen. The mechanism by which this occurs is unclear. To begin to understand the mechanism, we determined the role of the PMN chemokine receptor, CXCR2, in DSS-induced colitis by using CXCR2(-/-) mice or by neutralizing CXCR2. DSS was administered through drinking water to CXCR2(-/-) and BALB/c mice for 5 days followed by regular water for 1 day. In the neutralization study, mice were injected with control serum or goat anti-CXCR2 antiserum. BALB/c mice receiving DSS and control serum-injected mice receiving DSS lost weight and showed considerable clinical illness. Histological observation revealed submucosal edema, PMN infiltration into the submucosa and mucosa, extensive crypt damage with abscesses, and ulceration. In contrast, both the CXCR2(-/-) and anti-CXCR2 antiserum-treated mice gained weight and had significantly lower symptom scores. Histology of these mice showed submucosal edema but relatively intact crypt architecture and very few ulcers. Significantly fewer PMNs were found in the mucosa in anti-CXCR2 anti-serum compared with control serum-injected inflamed mice, but no significant difference in eosinophil infiltration was observed between the groups. Our experiments identify a role for CXCR2 in DSS-induced colitis and suggest that antagonizing CXCR2 provides some therapeutic efficacy, possibly by impeding PMN recruitment into the mucosa. Antagonizing CXCR2 may form the basis for therapeutic drugs directed at controlling colitis.
Farooq
Shukkur Muhammed
SM
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Stillie
RoseMarie
R
Svensson
Majlis
M
Svanborg
Catharina
C
Strieter
Robert M
RM
Stadnyk
Andrew W
AW
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*
D019138:Antibodies, Blocking; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D016264:Dextran Sulfate