MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury
Nicolas Deroide, … , Nathalie Kubis, Ziad Mallat
Nicolas Deroide, … , Nathalie Kubis, Ziad Mallat
Published February 1, 2013
Citation Information: J Clin Invest. 2013;123(3):1176-1181. https://doi.org/10.1172/JCI65167.
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Brief Report Inflammation

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 β3 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

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

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Figure 2

MFGE8 protects against postischemic cerebral injury through inhibition of inflammasome-mediated IL-1β production.

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MFGE8 protects against postischemic cerebral injury through inhibition o...
(A and B) rMFGE8 inhibits ATP-induced IL-1β production (A) and caspase-1 activity (B) (see Methods). Data are representative of 3 independent experiments for in vitro experiments. Results are given as relative optic density (R.O.D.). (C and D) Cerebral ischemia significantly increased brain IL-1β production (C) and caspase-1 activity (D) in mice treated with artificial cerebrospinal fluid vehicle. Supplementation with rMFGE8 blunted both IL-1β production and the increase of caspase-1 activity. (E) Representative photomicrographs of cresyl violet staining and infarct volume quantification in WT and Mfge8–/– mice, with or without treatment with IL-1 receptor antagonist (IL-1ra) (administered in artificial cerebrospinal fluid, used as vehicle). *P < 0.05; **P < 0.01; ***P < 0.001; n = 6 to 8 mice per group for in vivo experiments.