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

Cell. 2018 Jun 28;174(1):156-171.e16. doi: 10.1016/j.cell.2018.05.027. Epub 2018 Jun 14.

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.

Keywords: LRRC33; TGF-β; integrins; microglia; milieu molecules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Bone Marrow Transplantation
  • Brain / metabolism
  • Carrier Proteins / classification
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Integrins / metabolism
  • Kaplan-Meier Estimate
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / metabolism*
  • Mutagenesis, Site-Directed
  • Nervous System / metabolism*
  • Neurodegenerative Diseases / mortality
  • Neurodegenerative Diseases / pathology
  • Neurodegenerative Diseases / therapy
  • Phylogeny
  • Protein Binding
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Carrier Proteins
  • Integrins
  • Protein Precursors
  • Transforming Growth Factor beta
  • integrin alphavbeta8