MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury
Open Access
- 1 February 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (3), 1176-1181
- https://doi.org/10.1172/jci65167
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.Keywords
This publication has 26 references indexed in Scilit:
- Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosisProceedings of the National Academy of Sciences of the United States of America, 2007
- MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSFJCI Insight, 2007
- Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in MiceCirculation, 2007
- The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesisProceedings of the National Academy of Sciences of the United States of America, 2007
- DENDRITIC CELL-DERIVED EXOSOMES CONTAINING MILK FAT GLOBULE EPIDERMAL GROWTH FACTOR-FACTOR VIII ATTENUATE PROINFLAMMATORY RESPONSES IN SEPSISShock, 2006
- Lactadherin promotes VEGF-dependent neovascularizationNature Medicine, 2005
- Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient MiceScience, 2004
- Identification of Mouse Sperm SED1, a Bimotif EGF Repeat and Discoidin-Domain Protein Involved in Sperm-Egg BindingCell, 2003
- Role of IL-1α and IL-1β in Ischemic Brain DamageJournal of Neuroscience, 2001
- Corpse clearance defines the meaning of cell deathNature, 2000