TGFβ1 Increases Microglia-Mediated Engulfment of Apoptotic Cells Via Upregulation of the Milk Fat Globule-EGF Factor 8

Milk fat globule-epidermal growth factor-factor 8 (Mfge8) has been described as an essential molecule during microglia-mediated clearance of apoptotic cells via binding to phosphatidylserine residues and subsequent phagocytosis. Impaired uptake of apoptotic cells by microglia results in prolonged inflammatory responses and damage of healthy cells. Although the mechanisms of Mfge8-mediated engulfment of apoptotic cells are well understood, endogenous or exogenous factors that regulate Mfge8 expression remain elusive. Here, we describe that TGF1 increases the expression of Mfge8 and enhances the engulfment of apoptotic cells by primary mouse microglia in a Mfge8-dependent manner. Further, apoptotic cells are capable of increasing microglial TGF expression and release and shift the microglia phenotype toward alternative activation. Moreover, we provide evidence that Mfge8 expression is differentially regulated in microglia after classical and alternative activation and that Mfge8 is not able to exert direct antiinflammatory effects on LPS-treated primary microglia. Together, these results underline the importance of TGF1 as a regulatory factor for microglia and suggest that increased TGF1 expression in models of neurodegeneration might be involved in clearance of apoptotic cells via regulation of Mfge8 expression. GLIA 2015;63:142-153 Main Points Microglial Mfge8 expression and secretion is increased in the presence of TGF1 TGF1 enhances engulfment of apoptotic cells by microglia in an Mfge8-dependent manner