Interferon Regulatory Factor-1 Mediates Alveolar Macrophage Pyroptosis During LPS-Induced Acute Lung Injury in Mice

ABSTRACTPreviously, we demonstrated that pyroptosis in alveolar macrophages (AMs) plays an essential role in LPS-induced acute lung injury (ALI). However, the underlying mechanism remains largely unclear. Here we show that the absence of interferon regulatory factor 1 (IRF-1) in genetic knock-out mice strongly abrogates pyroptosis in AMs and alleviates the LPS-induced lung injury and systemic inflammation. Our study demonstrates that IRF-1 contributes to caspase-1 activation and ASC pyroptosome formation in AMs and leads to downstream inflammatory cytokine release, including that of IL-1β, IL-18 and HMGB1. The nuclear translocation of IRF-1 is linked to the presence of toll-like receptor 4 (TLR4). Our findings suggest that pyroptosis and the downstream inflammatory response in AMs induced by LPS is a process that is dependent on TLR4-mediated up-regulation of IRF-1. In summary, IRF-1 plays a key role in controlling caspase-1 dependent pyroptosis and inflammation.