Journal Article

MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury

Kubis, Nathalie, Lerouet, Dominique, Deroide, Nicolas, Ryffel, Bernhard, Nih, Lina, Margaill, Isabelle, Li, Xuan, Baker, Lauren, Poittevin, Marine, Tedgui, Alain, Harrison, James, Mallat, Ziad, Masters, Leanne, Iwakura, Yoichiro, Pocard, Marc, Van Vré, Emily

2013

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adenosine Triphosphate - metabolism / Adenosine Triphosphate - physiology / Animals / Antigens, Surface - genetics / Antigens, Surface - metabolism / Antigens, Surface - physiology / Brief Report / Caspase 1 - metabolism / Cells, Cultured / Cerebral ischemia / Development and progression / Genetic aspects / Glycoproteins / Immune response / Immunity, Innate / Infarction, Middle Cerebral Artery - immunology / Infarction, Middle Cerebral Artery - metabolism / Infarction, Middle Cerebral Artery - pathology / Inflammasomes - metabolism / Integrin beta3 - metabolism / Interleukin-1 / Interleukin-1beta - metabolism / Lipopolysaccharides - pharmacology / Macrophages - immunology / Macrophages - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Milk Proteins - genetics / Milk Proteins - metabolism / Physiological aspects / Receptors, Purinergic P2X7 - metabolism / Regulation