Genetic deficiency in the chemokine receptor CCR1 protects against acute Clostridium difficile toxin A enteritis in mice

Background & Aims: The role of the CC chemokine receptor (CCR) 1 in acute enteritis was investigated by subjecting CCR1 knockout mice to Clostridium difficile toxin A treatment. Methods: Toxin A or vehicle was injected into ileal loops in anesthetized wild-type, CCR1-/- and macrophage inhibitory protein (MIP)-1alpha(-/-) mice. After 1-4 hours, fluid accumulation was calculated, and the loops were processed for histology, myeloperoxidase activity, regulated on activation, normal T cell expressed and secreted (RANTES) production, and messenger RNA measurements. Results: Toxin A induced in all mice a significant (P < 0.05) increase in ileal fluid accumulation, epithelial damage, and neutrophil infiltration, with all parameters being significantly (P < 0.01) lower in CCR1(-/-) and MIP-1alpha(-/-) mice. Ileal messenger RNA expression of the CCR:1 ligands MIP-1alpha and RANTES and RANTES synthesis were increased in toxin A-treated wild-type mice. The RANTES antagonist Met-RANTES significantly (P < 0.01) reduced the toxin A-induced increases in ileal fluid accumulation and myeloperoxidase activity in wild-type mice. Conclusions: C. difficile toxin A-induced murine enteritis involves CCR1 and its ligands MIP-1alpha and RANTES, which may be important mediators of the neutrophil recruitment characterizing acute, enterotoxin-mediated enteritis.