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

• Yan Qin ^[1] ; Brian S. Garrison ^[1] ; Wenjiang Ma ^[1]
  1. [1] Boston Children´s Hospital
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 1, 2018, págs. 156-171
• Idioma: inglés
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• Resumen

  • 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.