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

Extracellular proTGF-beta is covalently linked to `` milieu'' molecules in the matrix or on cell surfaces and is latent until TGF-beta is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-alpha V beta 8-dependent TGF-beta activation. Lrrc33(-/-) mice lack CNS vascular abnormalities associated with deficiency in TGF-beta-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-b activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin- bearing cells and cells bearing milieu moleculeassociated TGF-beta provide localized and selective activation of TGF-beta.