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

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

Author information

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.

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

PMID:
29909984
PMCID:
PMC6089614
[Available on 2019-06-28]
DOI:
10.1016/j.cell.2018.05.027

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