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.

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…During classical microglial activation, LPS can significantly reduce MFGE8 expression (Fig 4C,D) while increasing phagocytic activity (Fig 4F). This is consistent with other past reports performed under WT conditions 18, 19, 20…”

“…It has also been shown to be a key regulator of C1q expression and synaptic pruning in the developing visual system 40. Besides, TGFb1 can also upregulate MFGE8 expression and increase microglia‐mediated engulfment of apoptotic cells 20. Hence, the increased TGFb signaling could potentially stimulate both C1q and MFGE8.…”

Exploring New Inflammatory Biomarkers and Pathways during LPS-Induced M1 Polarization

“…There are still controversial data concerning the protective/noxious role of MFG-E8. On one hand, MFG-E8 has been associated with microglia anti-inflammatory properties, as demonstrated by Spittau et al [75], when the cells were stimulated by TGF- β , in the MGF-E8 −/− mice showing an increased proinflammatory response [19], as well as in the septic mouse presenting downregulation of MFG-E8 levels [76]. On the other hand, Liu and colleagues [77] have demonstrated that MFG-E8 overexpression occurred concomitantly with TNF- α and IL-1 β upregulation.…”

Endocannabinoids drive the acquisition of an alternative phenotype in microglia

“…TGFb is a known inducer of the M2c phenotype and it is released by many cell types in the brain but mainly by microglia (Spittau et al, 2015). By using antagonists for CB1 and CB2 receptors, we have seen by RT-PCR that SOCS3 induction by TGFb at 6 h post-treatment was blocked (Suppl.…”

“…The acquired deactivated (M2c) phenotype is induced by the immunosuppressive cytokines, TGFb and IL-10, and it is mainly identified by the expression of SOCS3. Significantly, apoptotic cells are capable of enhancing microglial TGFb expression and release thereby shifting the microglia phenotype towards alternative activation M2c (Spittau et al, 2015). Indeed, it was recently reported that these phenotypes can be identified in microglia cultures (Chhor et al, 2013).…”