D-Dopachrome Tautomerase Promotes Astrocytic Cholesterol 25-Hydroxylase Expression Through the ERK/NF-κB Pathway Following Rat Spinal Cord Injury

Astrocytes act as crucial cellular centres of cholesterol synthesis and metabolism and help maintain homeostasis in the healthy CNS. Spinal cord injury (SCI) results in abnormalities in astrocytic cholesterol metabolism and excessive oxysterol accumulation, contributing to the activation of inflammation. However, the relevant regulatory mechanism involved in aberrant cholesterol metabolism by astrocytes has not been fully elucidated. In the present study, we demonstrated that SCI-induced d-DT protein levels increased synchronously with CH25H expression. Administration of the d-DT inhibitor 4-CPPC markedly decreased CH25H expression in astrocytes following SCI. d-DT facilitates CH25H production in astrocytes by activating the intracellular ERK/NF-κB pathway through binding to the CD74 receptor. Conditioned culture medium from astrocytes following the knockdown of astrocyte CH25H expression by siRNA reduced microglial migration. The inhibition of d-DT or CH25H activity reduces microglia/macrophage accumulation at the lesion site and improves motor functional recovery following SCI. Our results reveal a novel function of d-DT-mediated astrocytic CH25H activation, which modulates pathological microenvironments through the activation of inflammation. These data may provide a potential therapeutic strategy for CNS inflammation-associated diseases.