Silencing of TGFβ signalling in microglia results in impaired homeostasis

Abstract

TGFβ1 has been implicated in regulating functional aspects of several distinct immune cell populations including central nervous system (CNS) resident microglia. Activation and priming of microglia have been demonstrated to contribute to the progression of neurodegenerative diseases and, thus, underlie stringent control by endogenous regulatory factors including TGFβ1. Here, we demonstrate that deletion of Tgfbr2 in adult postnatal microglia does neither result in impairment of the microglia-specific gene expression signatures, nor is microglial survival and maintenance affected. Tgfbr2-deficient microglia were characterised by distinct morphological changes and transcriptome analysis using RNAseq revealed that loss of TGFβ signalling results in upregulation of microglia activation and priming markers. Moreover, protein arrays demonstrated increased secretion of CXCL10 and CCL2 accompanied by activation of immune cell signalling as evidenced by increased phosphorylation of TAK1. Together, these data underline the importance of microglial TGFβ signalling to regulate microglia adaptive changes.

NG2 glia are required for maintaining microglia homeostatic state

“…Previous studies indicated that TGF signaling played vital roles in maintaining microglia homeostasis (Butovsky et al 2014;Qin et al 2018;Zoller et al 2018). Interestingly, we found both the type-1 and type-2 TGFreceptors, which are highly expressed in homeostatic microglia, were notably downregulated after NG2 glia depletion (Fig.…”

“…Disrupting TGF signaling in microglia through conditional removal of TGF receptor 2 in the adult brain resulted in loss of microglia homeostasis and altered microglia response to stimulations (Zoller et al 2018). The action of TGFβ on microglia is highly selective and localized, with little spreading between neighboring cells (Qin et al 2018).…”

NG2 glia are required for maintaining microglia homeostatic state

“…Previous studies indicated that TGFβ signaling played vital roles in maintaining microglia homeostasis (Butovsky et al, ; Qin et al, ; Zoller et al, ). Interestingly, we found both the Type‐1 and Type‐2 TGFβ receptors, which are highly expressed in homeostatic microglia, were notably downregulated after NG2 glia depletion (Figure e).…”

“…Previous studies have suggested that TGFβ pathway is important for normal microglia development and suppressed in microglia associated with neurodegenerative diseases (Butovsky et al, ; Krasemann et al, ). Disrupting TGFβ signaling in microglia through conditional removal of TGFβ receptor 2 in the adult brain resulted in loss of microglia homeostasis and altered microglia response to stimulations (Zoller et al, ). The action of TGFβ on microglia is highly selective and localized, with little spreading between neighboring cells (Qin et al, ).…”

“…Disrupting TGFβ signaling in microglia through conditional removal of TGFβ receptor 2 in the adult brain resulted in loss of microglia homeostasis and altered microglia response to stimulations (Zoller et al, 2018). The action of TGFβ on microglia is highly selective and localized, with little spreading between neighboring cells (Qin et al, 2018).…”