Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis

Area of Science:

• Neuroimmunology
• Lipid Metabolism
• Vascular Biology

Background:

• The central nervous system (CNS) vasculature regulates immune cell entry during inflammatory diseases like multiple sclerosis (MS).
• Endothelial-derived factors influencing CNS immune responses are largely unknown.
• Oxysterols, produced by Cholesterol-25-hydroxylase (Ch25h), are bioactive lipids implicated in neuroinflammation.

Purpose of the Study:

• To investigate the role of Ch25h in CNS endothelial cells (ECs) in regulating neuroinflammation.
• To determine the impact of endothelial Ch25h on immune cell populations and experimental autoimmune encephalomyelitis (EAE).

Main Methods:

• Utilized floxed-reporter Ch25h knock-in mice to track Ch25h expression.
• Generated mice with Ch25h ablation specifically in CNS ECs.
• Analyzed lipid metabolism in inflamed CNS ECs and characterized myeloid cell populations.

Main Results:

• Ch25h is expressed in CNS ECs and myeloid cells.
• Ablation of Ch25h in CNS ECs attenuated EAE severity.
• Inflamed Ch25h-deficient CNS ECs exhibited altered lipid metabolism, promoting polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion.
• PMN-MDSCs suppressed encephalitogenic T lymphocyte proliferation.
• Combined endothelial Ch25h deficiency and immature neutrophil mobilization conferred near-complete protection against EAE.

Conclusions:

• CNS endothelial Ch25h plays a critical role in promoting neuroinflammation.
• Endothelial Ch25h regulates neuroinflammation by modulating the expansion of immunosuppressive myeloid cell populations.
• Targeting endothelial Ch25h represents a potential therapeutic strategy for CNS inflammatory diseases.