title: TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8.
abstract: 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 TGFβ1 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 TGFβ 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 TGFβ1 as a regulatory factor for microglia and suggest that increased TGFβ1 expression in models of neurodegeneration might be involved in clearance of apoptotic cells via regulation of Mfge8 expression.
authors.affiliation: Department of Molecular Embryology, Institute for Anatomy and Cell Biology, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Spittau
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rilka
authors.forename: Elsa
authors.initials: E
authors.lastname: Steinfath
authors.forename: Tanja
authors.initials: T
authors.lastname: Zöller
authors.forename: Kerstin
authors.initials: K
authors.lastname: Krieglstein
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D006017:Glycolipids / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D066292:Lipid Droplets; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D008894:Milk Proteins / Q000378:metabolism*; D010587:Phagocytosis / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000954:Antigens, Surface; D006017:Glycolipids; D006023:Glycoproteins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C110367:milk fat globule
keywords: Mfge8; TGFβ1; apoptotic cells; microglia; phagocytosis