Type I IFN receptor regulates neutrophil functions and innate immunity to Leishmania parasites

Type I IFNs exert diverse effector and regulatory functions in host immunity to viral and nonviral infections; however, the role of endogenous type I IFNs in leishmaniasis is unclear. We found that type I IFNR-deficient (IFNAR^-/-) mice developed attenuated lesions and reduced Ag-specific immune responses following infection with Leishmania amazonensis parasites. The marked reduction in tissue parasites, even at 3 d in IFNAR^-/- mice, seemed to be indicative of an enhanced innate immunity. Further mechanistic analyses indicated distinct roles for neutrophils in parasite clearance; IFNAR^-/- mice displayed a rapid and sustained infiltration of neutrophils, but a limited recruitment of CD11b⁺Ly-6C⁺ inflammatory monocytes, into inflamed tissues; interactions between IFNAR ^-/-, but not wild-type (WT) or STAT1^-/-, neutrophils and macrophages greatly enhanced parasite killing in vitro; and infected IFNAR ^-/- neutrophils efficiently released granular enzymes and had elevated rates of cell apoptosis. Furthermore, although coinjection of parasites with WT neutrophils or adoptive transfer of WT neutrophils into IFNAR ^-/- recipients significantly enhanced infection, the coinjection of parasites with IFNAR^-/- neutrophils greatly reduced parasite survival in WT recipients. Our findings reveal an important role for type I IFNs in regulating neutrophil/monocyte recruitment, neutrophil turnover, and Leishmania infection and provide new insight into innate immunity to protozoan parasites.