In this study we demonstrate that (i) in two independent mouse models of sepsis, platelets limit the clinical severity via the platelet ITAM receptor, CLEC-2; (ii) this effect of CLEC-2 is independent of thrombosis; (iii) the protective role of CLEC-2 is partially mediated by its interaction with podoplanin expressed on inflammatory macrophages but not kidney podocytes; and (iv) the CLEC-2-podoplanin interaction regulates immune cells infiltration and the inflammatory reaction at the site of infection. The gene discussed is CLEC1B; the disease is infection.