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
  • 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: [email protected].
  • 7. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
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.