Impaired innate immune response and enhanced pathology during Citrobacter rodentium infection in mice lacking functional P-selectin

Abstract

The selectin family of adhesion molecules mediates recruitment of immune cells to sites of inflammation which is critical for host resistance against infection. To characterize the role of selectins in host defence against Citrobacter rodentium infection, wild-type (WT) mice and mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), P-, E- and L-selectin were infected using a Citrobacter-induced colitis model. Infected mice lacking PSGL-1 or P-selectin showed a more pronounced morbidity associated with higher bacterial load, elevated IL-12 p70, TNF-alpha, IFN-gamma, MCP-1 and IL-6 production, more severe inflammation and surprisingly higher leucocyte infiltration in the guts than WT control. Recruitment of neutrophils and macrophages and caecal inflammation were drastically reduced in infected P-selectin knockout mice receiving blocking monoclonal antibodies to ICAM-1 or LFA-1, indicating that these adhesion molecules may compensate for the loss of selectins in leucocyte recruitment. Furthermore, the adaptive immune response in mice lacking PSGL-1 or P-selectin remained functional since these infected mice were capable of eradicating the bacteria and being protected upon re-challenge with C. rodentium. These data demonstrate a definitive phenotypic impairment of innate response in mice lacking PSGL-1 or P-selectin, and suggest that these adhesion molecules are important in host innate immune response against Citrobacter infection.