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

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.