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Type I interferons license caspase-11-dependent NLRP3 inflammasome activation by Gram-negative bacteria

Type I interferons license caspase-11-dependent NLRP3 inflammasome activation by Gram-negative bacteria

Type I interferon response represents the hall mark of innate immune effector mechanisms. Although it has been well-documented that type I interferons are key players in coordinating anti-viral immunity, their role in bacterial infections remains poorly defined. Systemic infections with bacteria are characterized by high mortality rates due to the sepsis syndrome , a widespread and uncontrolled inflammatory response. The objective of this study was to determine the role of type I interferons in eliciting innate immune defense against bacterial pathogens. Here, we have identified a novel type I interferon pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. Various knock-out mice and macrophages from them were used. Immunoblotting, ELISAs and qPCR were used to assess immune responses. A systematic investigation of inflammasome activation by enterohemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium, Gram-negative enteropathogens, revealed a role for TLR4 and TRIF in NLRP3 inflammasome activation as macrophages lacking TLR4 or TRIF failed to process caspase-1 and secrete IL-1? and IL-18. TRIF signaling downstream of TLR4 triggers interferon regulatory factor (IRF)-3 dependent IFN-? production. Indeed, TLR4-TRIF signaling was found to be essential for IFN-? production elicited by EHEC and C. rodentium. Importantly, we found that EHEC and C. rodentium-induced IFN-? subsequently targets the activation of caspase-11, which is a member of the caspase-1 subfamily of inflammatory proteases. A recent study identified caspase-11 as a key regulator of caspase-1 activation and IL-1?/IL-18 production in response to a set of enteric pathogens [1]. Unlike other caspases, caspase-11 is unique in that it is highly inducible. We determined that type I interferon regulates caspase-11 activation by up-regulating caspase-11 expression in an autocrine/paracrine manner in EHEC and C. rodentium infection. Remarkably the transcriptional induction of caspase-11 by IFN-? was both necessary and sufficient to promote caspase-11 auto-activation suggesting a model wherein transcriptional induction of pro-caspase-11 is coupled to its auto-activation. Caspase-11 activation via the TLR4-TRIF-IFN-? pathway ultimately synergizes with the NLRP3 pathway to coordinate caspase-1 dependent IL-1? and IL-18 processing and secretion. The requirement for IFN-?-caspase-11 axis for NLRP3 inflammasome activation was found to be highly specific for Gram-negative but not Gram-positive bacteria. Finally, in a well-established acute bacterial peritonitis and shock model using E. coli, we determined that IFN-?-caspase-11 pathway is essential for E. coli induced IL-1? and IL-18 production not only in vitro but also in vivo. Thus, the identification of type I interferon as a regulator of caspase-11-dependent NLRP3 inflammasome activation provides new insights into the integration of TLR and NLR pathways during Gram-negative bacterial infections and unveils new targets that might be manipulated to prevent uncontrolled inflammation during septic shock.

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