Serum LDL Promotes Microglial Activation and Exacerbates Demyelinating Injury in Neuromyelitis Optica Spectrum Disorder
Man Chen1,2,3 · Yun‑Hui Chu1,2 · Wen‑Xiang Yu1,2 · Yun‑Fan You1,2 · Yue Tang1,2 · Xiao‑Wei Pang1,2 · Hang Zhang1,2 · Ke Shang1,2 · Gang Deng1,2 · Luo‑Qi Zhou1,2 · Sheng Yang1,2 · Wei Wang1,2 · Jun Xiao1,2 · Dai‑Shi Tian1,2 · Chuan Qin1,21 Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2 Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
3 Department of Neurology, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.
Keywords
Neuromyelitis optica spectrum disorder; Low-density lipoprotein; Microglia
