title: MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury.
abstract: Milk fat globule-EGF 8 (MFGE8) plays important, nonredundant roles in several biological processes, including apoptotic cell clearance, angiogenesis, and adaptive immunity. Several recent studies have reported a potential role for MFGE8 in regulation of the innate immune response; however, the precise mechanisms underlying this role are poorly understood. Here, we show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell-induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β(3) and P2X7 receptor interactions in primed cells. Itgb3 deficiency in macrophages abrogated the inhibitory effect of MFGE8 on ATP-induced IL-1β production. In a setting of postischemic cerebral injury in mice, MFGE8 deficiency was associated with enhanced IL-1β production and larger infarct size; the latter was abolished after treatment with IL-1 receptor antagonist. MFGE8 supplementation significantly dampened caspase-1 activation and IL-1β production and reduced infarct size in wild-type mice, but did not limit cerebral necrosis in Il1b-, Itgb3-, or P2rx7-deficient animals. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production.
authors: Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors: Nicolas
authors: N
authors: Deroide
authors: Xuan
authors: X
authors: Li
authors: Dominique
authors: D
authors: Lerouet
authors: Emily
authors: E
authors: Van Vré
authors: Lauren
authors: L
authors: Baker
authors: James
authors: J
authors: Harrison
authors: Marine
authors: M
authors: Poittevin
authors: Leanne
authors: L
authors: Masters
authors: Lina
authors: L
authors: Nih
authors: Isabelle
authors: I
authors: Margaill
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Bernhard
authors: B
authors: Ryffel
authors: Marc
authors: M
authors: Pocard
authors: Alain
authors: A
authors: Tedgui
authors: Nathalie
authors: N
authors: Kubis
authors: Ziad
authors: Z
authors: Mallat
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D007113:Immunity, Innate; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D058847:Inflammasomes; D039661:Integrin beta3; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; C546469:P2rx7 protein, mouse; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D020170:Caspase 1