Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 3, Pages 1176-1181Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65167
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Funding
- British Heart Foundation
- Fondation pour la Recherche Medicale, France
- ERC Starting Grant
- British Heart Foundation [RG/10/001/27643] Funding Source: researchfish
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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-1 beta production. MFGE8 inhibited necrotic cell-induced and ATP-dependent IL-1 beta production by macrophages through mediation of integrin beta(3) and P2X7 receptor interactions in primed cells. Itgb3 deficiency in macrophages abrogated the inhibitory effect of MFGE8 on ATP-induced IL-1 beta production. In a setting of postischemic cerebral injury in mice, MFGE8 deficiency was associated with enhanced IL-1 beta 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-1 beta 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-1 beta production.
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