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Therapeutic effect of blocking CXCR2 on neutrophil recruitment and dextran sodium sulfate-induced colitis
Shukkur Muhammed Farooq1, RoseMarie Stillie, Majlis Svensson
1Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
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.
Insights
The chemokine receptor CXCR2 plays a key role in dextran sodium sulfate (DSS)-induced colitis by promoting neutrophil infiltration. Blocking CXCR2 in mice reduced colitis severity and inflammation, suggesting therapeutic potential.
Area of Science:
- Immunology
- Gastroenterology
- Inflammation Research
Background:
- Dextran sodium sulfate (DSS)-induced colitis in mice involves neutrophil infiltration into the colon.
- The precise mechanism driving this neutrophil recruitment remains incompletely understood.
Purpose of the Study:
- To investigate the role of the chemokine receptor CXCR2 in the pathogenesis of DSS-induced colitis.
- To evaluate the therapeutic potential of targeting CXCR2 in this colitis model.
Main Methods:
- Utilized CXCR2-deficient (CXCR2(-/-)) mice and a CXCR2-neutralizing antibody in a DSS-induced colitis model.
- Administered DSS orally and assessed clinical signs, weight loss, and histological changes.
- Quantified neutrophil infiltration in the colonic mucosa.
Main Results:
- CXCR2(-/-) mice and mice treated with anti-CXCR2 antiserum exhibited significantly reduced weight loss and clinical symptoms compared to controls.
- Histological analysis revealed less severe crypt damage, fewer ulcers, and reduced neutrophil infiltration in CXCR2-targeted groups.
- Eosinophil infiltration was not significantly affected by CXCR2 antagonism.
Conclusions:
- CXCR2 is crucial for neutrophil recruitment and the exacerbation of DSS-induced colitis.
- Antagonizing CXCR2 demonstrates therapeutic efficacy by mitigating inflammation and tissue damage.
- Targeting CXCR2 may offer a viable therapeutic strategy for managing colitis.
