PMC:3291650 / 7120-9432 JSONTXT

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The relevance of these findings for human disease has recently been illustrated through the identification of polymorphisms in the A20 locus that are associated with several autoimmune diseases and chronic inflammation [45]. In contrast to its well established function in the regulation of proinflammatory responses, the role of A20 in the regulation of antiviral immune responses is less well described and limited to a number of in vitro studies using overexpression or silencing in specific cell lines, indicating that A20 may regulate RIG-I- and TLR3-induced signaling to NF-κB and IRF-3 [49]–[52]. However, the precise in vivo role of A20 in the response to viral infection remains to be clarified. Using myeloid cell specific A20 knockout mice (A20myel-KO) that were recently generated in our lab and primary cells derived of these mice, we here provide evidence that A20 is a crucial negative regulator of IAV-induced proinflammatory and antiviral signaling in macrophages. Interestingly, A20myel-KO mice show enhanced survival and reduced morbidity in response to IAV lung infection compared to wild type mice. Protection against IAV in A20myel-KO mice is associated with increased cytokine and chemokine production, augmented recruitment of innate immune cells such as neutophils and alveolar macrophages, and enhanced viral clearance. 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