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.

Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease

“…19 Interestingly, XIAP also has been shown to be critical for toll-like receptor-modulated signaling in response to infection. 20 The patient's ascending inflammation is consistent with a maladaptive response to commensal organisms. The diagnosis of IBD in a patient with a mutation in XIAP suggests a broader role for this gene in mucosal immune regulation.…”

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

“…In addition, the loss of XIAP may influence immune cell activation resulting in alterations in pro-inflammatory cytokine production and cell survival in murine studies [33][34][35]. Because hypersecretion of IL-18 has been reported to play important roles in the pathogenesis of HLH [36], sustained elevation of IL-18 and its marked exacerbation on HLH in patients with XIAP deficiency would be an additional possibility to explain HLH susceptibility in this disease.…”

Inability to resolve specific infection generates innate immunodeficiency syndrome in Xiap−/− mice

“…We showed that TNF-a/IL-6 production induced by TLR2, TLR3, TLR4, or TLR7/8 was normal in Xiap 2/2 BMDMs, and XIAP deficiency did not affect TLR-induced NF-kB activation in T cells and macrophages, consistent with several recent reports. 16,[20][21][22] XIAP deficiency impaired only NF-kB activating processes that are mediated by BCL10, such as those stimulated by dectin-1, TCR, EGF, or LPA (Figures 1 and 3). Our data also agree with the observations that TNF-a-triggered NF-kB activation is normal in BCL10-knockout cells 40 and that LPS-induced NF-kB activation is not affected by deficiency in CARD9, 23 the BCL10-binding partner.…”

“…[13][14][15] Notably, Xiap 2/2 mice are sensitive to infection of Listeria monocytogenes, with impaired innate immune responses and defective activation in macrophages. 16 XIAP is also known to activate nuclear factor (NF)-kB independent of the inactivation of caspase. 12,[17][18][19] The requirement of XIAP in NF-kB activation is stimuli selective, and XIAP is involved in nonobese diabetic (NOD)2-initiated NF-kB activation but is also dispensable in tumor necrosis factor (TNF)-a-and lipopolysaccharide (LPS)-induced NF-kB activation.…”