A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System

Abstract

Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33 mice lack CNS vascular abnormalities associated with deficiency in TGF-β-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months. Whole bone marrow transplantation results in selective repopulation of Lrrc33 brains with WT microglia and halts disease progression. The phenotypes of WT and Lrrc33 microglia in the same brain suggest that there is little spreading of TGF-β activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin-bearing cells and cells bearing milieu molecule-associated TGF-β provide localized and selective activation of TGF-β.

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). This process is noncell-autonomous and relies on interactions between microglia and integrin αvβ8-bearing cells in the brain (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).…”

“…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, ). This process is non‐cell‐autonomous and relies on interactions between microglia and integrin αvβ8‐bearing cells in the brain (Qin et al, ).…”

“…The action of TGFβ on microglia is highly selective and localized, with little spreading between neighboring cells (Qin et al, ). This process is non‐cell‐autonomous and relies on interactions between microglia and integrin αvβ8‐bearing cells in the brain (Qin et al, ). High‐throughput gene expression studies have suggested that NG2 glia express high levels of both subunits of integrin αvβ8 (Zhang et al, ), as well as TGFβs (Zhang, Denham, & Thies, ).…”