Zbp1 Governs The Inflammasome-Independent Il-1 Alpha And Neutrophil Inflammation That Play A Dual Role In Anti-Influenza Virus Immunity

y Influenza A virus (IAV) triggers the infected lung to produce IL-1 and recruit neutrophils. Unlike IL-1 beta, however, little is known about IL-1 alpha in terms of its mechanism of induction, action and physiological relevance to the host immunity against IAV infection. In particular, whether Z-DNA-binding protein 1 (ZBP1), a key molecule for IAV-induced cell death, is involved in the IL-1 alpha induction, neutrophil infiltration and the physiological outcome has not been elucidated. Here, we show in a murine model that the IAV-induced IL-1 alpha is mediated solely by ZBP1, in an NLRP3-inflammasome-independent manner, and is required for the optimal IL-1 beta production followed by the formation of neutrophil extracellular traps (NETs). During IAV infection, ZBP1 displays a dual role in anti-IAV immune responses mediated by neutrophils, resulting in either protective or pathological outcomes in vivo. Thus, ZBP1-mediated IL-1 alpha production is the key initial step of IAV-infected NETs, regulating the duality of the consequent lung inflammation.