MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury

J Clin Invest. 2013 Mar;123(3):1176-81. doi: 10.1172/JCI65167. Epub 2013 Feb 1.


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 inflammasome-induced IL-1β production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / physiology
  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Antigens, Surface / physiology*
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Immunity, Innate
  • Infarction, Middle Cerebral Artery / immunology*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Inflammasomes / metabolism*
  • Integrin beta3 / metabolism
  • Interleukin-1beta / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Milk Proteins / genetics
  • Milk Proteins / metabolism
  • Receptors, Purinergic P2X7 / metabolism


  • Antigens, Surface
  • Inflammasomes
  • Integrin beta3
  • Interleukin-1beta
  • Lipopolysaccharides
  • Mfge8 protein, mouse
  • Milk Proteins
  • P2rx7 protein, mouse
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate
  • Caspase 1