XIAP Regulates Cytosol-Specific Innate Immunity to Listeria Infection

Abstract

The inhibitor of apoptosis protein (IAP) family has been implicated in immune regulation, but the mechanisms by which IAP proteins contribute to immunity are incompletely understood. We show here that X-linked IAP (XIAP) is required for innate immune control of Listeria monocytogenes infection. Mice deficient in XIAP had a higher bacterial burden 48 h after infection than wild-type littermates, and exhibited substantially decreased survival. XIAP enhanced NF-κB activation upon L. monocytogenes infection of activated macrophages, and prolonged phosphorylation of Jun N-terminal kinase (JNK) specifically in response to cytosolic bacteria. Additionally, XIAP promoted maximal production of pro-inflammatory cytokines upon bacterial infection in vitro or in vivo, or in response to combined treatment with NOD2 and TLR2 ligands. Together, our data suggest that XIAP regulates innate immune responses to L. monocytogenes infection by potentiating synergy between Toll-like receptors (TLRs) and Nod-like receptors (NLRs) through activation of JNK- and NF-κB–dependent signaling. During a bacterial infection, the innate immune response plays two critical roles: controlling early bacterial replication and stimulating the adaptive immune response to clear infection. Host recognition of bacterial components occurs through pathogen sensors at the cell surface or within the host cell cytosol. Inhibitor of apoptosis proteins (IAPs) have been recently implicated in immune regulation, but how IAPs contribute to immunity is incompletely understood. Here, we show that X-linked IAP (XIAP) protects against infection by the cytosolic bacterial pathogen, Listeria monocytogenes, which causes severe disease in neonates and immunocompromised individuals. We found that XIAP enhanced MAP kinase signaling in L. monocytogenes infected macrophages, a key innate immune effector cell. Additionally, XIAP enabled synergy between cell surface and cytosolic bacterial sensors, promoting increased gene expression of proinflammatory cytokines. Our findings suggest that IAPs are integral regulators of innate immune signaling, coordinating extracellular and intracellular responses against microbial components to control bacterial infection.