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.
Highlights
The inhibitor of apoptosis (IAP) family of proteins plays a key role in cellular signaling, such as apoptosis, by binding to proapoptotic proteins, interrupting the intrinsic programmed cell death pathway and activating anti-apoptotic mechanisms [1,2,3]
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
Summary
The inhibitor of apoptosis (IAP) family of proteins plays a key role in cellular signaling, such as apoptosis, by binding to proapoptotic proteins, interrupting the intrinsic programmed cell death pathway and activating anti-apoptotic mechanisms [1,2,3]. Innate immune signaling pathways are well conserved from Drosophila to humans, suggesting that IAP proteins may play a role in mammalian innate immunity [8]. This hypothesis is consistent with a study demonstrating that cIAP2 exacerbates endotoxic shock in mice by controlling macrophage apoptosis [9]. XIAP-deficient mice do not appear to have striking defects in apoptosis, the role of XIAP in vivo is not yet clearly understood [20]
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