MFGE8 inhibits inflammasome-induced IL-1[Beta] production and limits postischemic cerebral injury

• Published in: The Journal of clinical investigation 2013-03, Vol.123 (3), p.1176
• Main Authors: Deroide, Nicolas, Li, Xuan, Lerouet, Dominique, Van Vré, Emily, Baker, Lauren, Harrison, James, Poittevin, Marine, Masters, Leanne, Nih, Lina, Margaill, Isabelle, Iwakura, Yoichiro, Ryffel, Bernhard, Pocard, Marc, Tedgui, Alain, Kubis, Nathalie, Mallat, Ziad
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antigens; Biomedical research; Cerebrospinal fluid; Cytokines; Ischemia; Sepsis
• ISSN: 0021-9738; 1558-8238

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^sub 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. [PUBLICATION ABSTRACT]