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Published on: November 16, 2011
A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System
Yan Qin1, Brian S Garrison2, Wenjiang Ma1
1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Microglia LRRC33 acts as a milieu molecule, enabling localized TGF-β activation. Lrrc33 deficiency in mice causes neurodegeneration, highlighting LRRC33
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Extracellular latent TGF-β is activated by integrins after release from milieu molecules.
- Microglia play crucial roles in central nervous system (CNS) homeostasis and disease.
Purpose of the Study:
- To investigate the role of LRRC33 in microglia and its function in TGF-β activation.
- To determine the in vivo consequences of Lrrc33 deficiency in the CNS.
Main Methods:
- Utilized Lrrc33 knockout (Lrrc33-/-) mice.
- Employed whole bone marrow transplantation to assess microglial repopulation.
- Analyzed CNS pathology, including vascular abnormalities, microglial phenotype, and axonal integrity.
Main Results:
- Microglial LRRC33 functions as a milieu molecule, mediating localized, integrin-αVβ8-dependent TGF-β activation.
- Lrrc33-/- mice exhibit reactive microglia and develop progressive neurodegeneration, including paraparesis and axonal loss.
- Selective repopulation of Lrrc33-/- brains with wild-type (WT) microglia halted disease progression.
- Lack of TGF-β spread between microglia suggests localized activation.
Conclusions:
- LRRC33 on microglia is essential for localized TGF-β activation, crucial for CNS health.
- Microglial LRRC33 deficiency leads to neurodegenerative pathology.
- Targeting microglial LRRC33 may offer therapeutic strategies for CNS disorders involving TGF-β dysregulation.
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