2. Academic Validation
  3. A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System

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.
Yan Qin 1,  Brian S Garrison 2,  Wenjiang Ma 1,  Rui Wang 1,  Aiping Jiang 1,  Jing Li 1,  Meeta Mistry 3,  Roderick T Bronson 4,  Daria Santoro 1,  Charlotte Franco 1,  Daisy A Robinton 5,  Beth Stevens 5,  Derrick J Rossi 2,  Chafen Lu 6,  Timothy A Springer 7
Affiliations

Affiliations

  • 1 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • 2 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Department of Stem Cell and Regenerative Biology, Boston, MA 02115, USA.
  • 3 Harvard School of Public Health, Boston, MA 02115, USA.
  • 4 Harvard Medical School, Boston, MA 02115, USA.
  • 5 Harvard Medical School, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
  • 6 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: lu@crystal.harvard.edu.
  • 7 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: springer@crystal.harvard.edu.
PMID: 29909984 DOI: 10.1016/j.cell.2018.05.027
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.

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