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CXCR2 knockout mice are protected against DSS-colitis-induced acute kidney injury and inflammation
Punithavathi Ranganathan1, Calpurnia Jayakumar, Santhakumar Manicassamy
1Dept. of Medicine/Vascular Biology Center, CB-3702, Georgia Regents Univ., 1459 Laney-Walker Blvd, Augusta, GA 30912. gramesh@gru.edu.
Abstract:
Organ cross talk exists in many diseases of the human and animal models of human diseases. A recent study demonstrated that inflammatory mediators can cause acute kidney injury and neutrophil infiltration in a mouse model of dextran sodium sulfate (DSS)-colitis. However, the chemokines and their receptors that may mediate distant organ effects in colitis are unknown. We hypothesized that keratinocyte chemoattractant (KC)/IL-8 receptor chemokine (C-X-C motif) ligand 2 (CXCL2) mediates DSS-colitis-induced acute kidney injury. Consistent with our hypothesis, wild-type (WT) mice developed severe colitis with DSS treatment, which was associated with inflammatory cytokine and chemokine expression and neutrophil infiltration in the colon. DSS-colitis in WT was accompanied by acute kidney injury and enhanced expression of inflammatory cytokines in the kidney. However, CXCR2 knockout mice were protected against DSS-colitis as well as acute kidney injury. Moreover, the expression of cytokines and chemokines and neutrophil infiltration was blunted in CXCR2 knockout mice in the colon and kidney. Administration of recombinant KC exacerbated DSS-colitis-induced acute kidney injury. Our results suggest that KC/IL-8 and its receptor CXCR2 are critical and major mediators of organ cross talk in DSS colitis and neutralization of CXCR2 will help to reduce the incidence of acute kidney injury due to ulcerative colitis and Crohn's disease in humans.
Insights
Keratinocyte chemoattractant (KC) and its receptor CXCR2 mediate kidney injury during colitis. Blocking CXCR2 protects against colitis and associated kidney damage, offering therapeutic potential for inflammatory bowel diseases.
Area of Science:
- Immunology
- Gastroenterology
- Nephrology
Background:
- Organ cross talk is implicated in various diseases.
- Inflammatory mediators can induce acute kidney injury and neutrophil infiltration during dextran sodium sulfate (DSS)-colitis.
- The specific chemokines and receptors mediating distant organ effects in colitis remain largely unknown.
Purpose of the Study:
- To investigate the role of keratinocyte chemoattractant (KC)/CXCL2 and its receptor CXCR2 in mediating acute kidney injury during DSS-colitis.
- To determine if KC/CXCL2-CXCR2 axis is a critical mediator of organ cross talk in DSS-colitis.
Main Methods:
- Induction of DSS-colitis in wild-type (WT) and CXCR2 knockout (KO) mice.
- Assessment of colitis severity, inflammatory cytokine and chemokine expression, and neutrophil infiltration in the colon and kidney.
- Administration of recombinant KC to WT mice to evaluate its effect on DSS-colitis-induced kidney injury.
Main Results:
- WT mice developed severe colitis with DSS, accompanied by kidney injury and elevated inflammatory markers in both organs.
- CXCR2 KO mice were protected from DSS-colitis and associated acute kidney injury.
- Neutrophil infiltration and inflammatory cytokine/chemokine expression were significantly reduced in both the colon and kidney of CXCR2 KO mice.
- Recombinant KC administration worsened DSS-colitis-induced kidney injury.
Conclusions:
- KC/IL-8 and its receptor CXCR2 are critical mediators of organ cross talk in DSS colitis.
- Targeting the CXCR2 pathway may reduce the incidence of acute kidney injury associated with ulcerative colitis and Crohn's disease.
