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.
Eigenbrod
Tatjana
T
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Park
Jong-Hwan
JH
Harder
Jürgen
J
Iwakura
Yoichiro
Y
Núñez
Gabriel
G
D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000276:immunology; D010529:Peritoneal Cavity / Q000473:pathology
D054360:Chemokine CXCL1; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D015850:Interleukin-6