The LncRNA AK018453 regulates TRAP1/Smad signaling in IL‐17‐activated astrocytes: A potential role in EAE pathogenesis

The pro‐inflammatory cytokine interleukin 17 (IL‐17), that is mainly produced by Th17 cells, has been recognized as a key regulator in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Reactive astrocytes stimulated by proinflammatory cytokines including IL‐17 are involved in blood brain barrier destruction, inflammatory cells infiltration and spinal cord injury. However, the role of long non‐coding RNAs (lncRNAs) induced by IL‐17 in the pathogenesis of MS and EAE remains unknown. Herein, we found that an IL‐17‐induced lncRNA AK018453 promoted TGF‐β receptor‐associated protein 1 (TRAP1) expression and Smad‐dependent signaling in mouse primary astrocytes. Knockdown of AK018453 significantly suppressed astrocytosis, attenuated the phosphorylation of Smad2/3, reduced NF‐κB p65 and CBP/P300 binding to the TRAP1 promoter, and diminished pro‐inflammatory cytokine production in the IL‐17‐treated astrocytes. AK018453 knockdown in astrocytes by a lentiviral vector in vivo dramatically inhibited inflammation and prevented the mice from demyelination in the spinal cord during the progression of EAE. Together, these results suggest that AK018453 regulates IL‐17‐dependent inflammatory response in reactive astrocytes and potentially promotes the pathogenesis of EAE via the TRAP1/Smad pathway. Targeting this pathway may have a therapeutic potential for intervening inflammatory demyelinating diseases. Main Points AK018453, an upregulated lncRNA in IL‐17‐activated astrocytes, enhances TRAP1 expression, triggers Smad signaling in the reactive astrocytes and in EAE mice. AK018453 knockdown in astrocytes dramatically inhibited inflammation and prevented the mice from demyelination during the progression of EAE.