HPGD: An Intermediate Player in Microglial Polarization and Multiple Sclerosis Regulated by Nr4a1

Area of Science:

• Neuroimmunology
• Molecular Biology
• Inflammation Research

Background:

• Multiple sclerosis (MS) is a neuroinflammatory disease.
• Microglia polarization plays a critical role in MS pathogenesis.
• The role of 15-Hydroxyprostaglandin dehydrogenase (HPGD) in MS and its regulation by Nr4a1 were previously unknown.

Purpose of the Study:

• To investigate the role of HPGD in microglia polarization.
• To determine if HPGD mediates the inhibitory effects of Nr4a1 on experimental autoimmune encephalomyelitis (EAE).
• To explore HPGD's impact on PPARγ activation in EAE.

Main Methods:

• Induction of EAE in C57BL/6 mice using MOG35-55 peptide.
• In vitro M1/M2 microglia polarization using BV-2 cells.
• Analysis of spinal cord pathology, gene expression, and PPARγ activation.
• Chromatin immunoprecipitation (ChIP) and pull-down assays to verify protein interactions.

Main Results:

• HPGD expression was downregulated in the spinal cords of EAE mice.
• HPGD overexpression alleviated EAE progression by inhibiting M1 and promoting M2 microglia polarization.
• Nr4a1 directly binds to the HPGD promoter, increasing its expression and reversing Nr4a1's effects on microglia polarization.

Conclusions:

• HPGD is regulated by Nr4a1 and plays a crucial role in modulating microglia polarization.
• HPGD inhibits EAE progression by shifting M1/M2 polarization and activating the PPARγ signaling pathway.
• HPGD represents a potential therapeutic target for MS treatment.