Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells.

Endogenous danger signals released from necrotic cells are thought to be sensed by phagocytes leading to secretion of IL-1alpha and neutrophilic recruitment. However, the mechanisms for IL-1alpha production and IL-1alpha-mediated sterile inflammation remain poorly understood. We report here that necrotic cell extracts elicited little secretion of CXCL1 and IL-6 from macrophages but robust production in mesothelial cells. The induction of CXCL1 as well as activation of NF-kappaB and MAPKs by cytosolic extracts required the presence of IL-1alpha in the necrotic cell. Conversely, expression of IL-1R and MyD88 but not IL-1alpha, RICK, TLR2, TLR4, TRIF, or inflammasome components in mesothelial cells was critical for the production of CXCL1. Furthermore, IL-1alpha was critical to induce the recruitment of neutrophils in the peritoneal cavity via CXCR2. These studies show that IL-1alpha is a key danger signal released from necrotic cells to trigger CXCL1 secretion and recruitment of neutrophils via IL-1R/MyD88 on neighboring mesothelial cells.