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 inflammasomeinduced IL-1β production.

Protective Effect of MFG-E8 after Cutaneous Ischemia–Reperfusion Injury

“…These findings suggest that hypoxia in ischemic areas might be associated with the enhancement of MFG-E8 expression in pericytes/vascular SMCs and ECs. Previous studies have reported that MFG-E8 mRNA and protein expression in organs, including the kidney, liver, and gut, were significantly decreased by I/R Wu et al, 2012;Deroide et al, 2013;Matsuda et al, 2013). Consistent with these previous results, MFG-E8 expression in cutaneous I/R areas was decreased by 0.5-fold at 72 hours after reperfusion.…”

“…Recent studies revealed that MFG-E8 significantly reduces inflammation and protects tissue injury after I/R in several organs including the brain, liver, kidney, and gut Wu et al, 2012;Deroide et al, 2013;Matsuda et al, 2013). These studies demonstrated that MFG-E8 mRNA and protein expression in organs, including kidney, liver, and gut, were significantly decreased by I/R, and that treatment with rMFG-E8 recovered organ dysfunction and suppressed inflammatory responses.…”

Phagocytosis executes delayed neuronal death after focal brain ischemia

“…Of note, two studies investigating models of permanent cerebral ischemia have reported protective effects mediated by MFG-E8 through modulation of the inflammatory response. One study reported enhanced IL-1β production and larger infarcts in Mfge8 knockout mice (50), whereas the other correspondingly reported suppression of inflammation after intravenous treatment with recombinant MFG-E8 and reduced infarct size (51). In contrast, we could not detect any significant changes in the inflammatory response after focal cerebral ischemia as measured by the number of activated microglia, as well as the release of inflammatory mediators both in vitro and in vivo (Figs.…”

The Complexity of the Innate Immune System Activation in Stroke Pathogenesis

“…In stroke, the release of DAMPs by the ischemic tissue mediates the activation of PRRs in the CNS. Some of these pathways have been demonstrated to mediate injury following cerebral ischemia Faraco et al, 2007;Qiu et al, 2010 Peroxiredoxins TLR2 and TLR4 Shichita et al, 2012 Heat shock proteins TLR2 and TLR4 Brea et al, 2011 Fibrin/fibrinogen TLR2 and TLR4 Zhang et al, 2012 Extracellular ATP NLRs (P2X7 pathway) Deroide et al, 2013 Histone deacetylase subunit SAP130 CLRs Suzuki et al, 2013 Abbreviations: DAMP, damage-associated molecular pattern; PRR, pattern recognition receptor; HMGB1, high-mobility group box-1; TLR, Toll-like receptor; NLRs, NOD-like receptors; P2X7, purinergic receptor P2X, ligand-gated ion channel 7; CLRs, C-type lectin receptors.…”

“…In agreement with this, recent findings indicate that the milk fat globule-EGF 8 (MFGE8), a secretory glycoprotein that binds to anionic phospholipids, extracellular matrices, and integrins, mediates a neuroprotective effect in brain ischemia by inhibition of the activity of the inflammasome. These effects are attributed to the ability of MFGE8 to limit P2X7 receptor-dependent IL-1β production (Deroide et al, 2013). In this context, direct inhibition of inflammasome activation using antibodies against NRLP1, a member of the NLR family, also induces neuroprotection after stroke (Abulafia et al, 2009).…”