부산대학교 도서관

ABSTRACTHeme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by the Hmox1gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (M?) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1-/-) mice are more susceptible to intravenous Mycobacterium aviuminfection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1+/+) controls. Furthermore, Hmox1-/-mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection with Mycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed in M. avium-infected Hmox1-/-versus Hmox1+/+SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected M?, an effect mimicked by exogenous heme administration to M. avium-infected wild-type M? in vitroor to mice in vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in M?, contributing critically to host resistance to Mycobacteriuminfection.