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

Abstract

The pro-inflammatory cytokine interleukin 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 Smaddependent 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 proinflammatory 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.

Multiple Sclerosis: Roles of miRNA, lcnRNA, and circRNA and Their Implications in Cellular Pathways

“…The results suggest lncRNA AK018453 and the TRAP1/Smad pathway play crucial roles in EAE pathogenesis. They might be a potential therapeutic target for MS treatment [131].…”

Assessing the suitability of long non-coding RNAs as therapeutic targets and biomarkers in SARS-CoV-2 infection

“…One potential target is AK018453, an IL-17-induced lncRNA that carries out the effect of IL-17 by promoting gene expression through TRAF1/Smad pathway. AK018453 knockdown was also reported to reduce pro-inflammatory cytokine production in the IL-17-treated astrocytes ( Zhang et al, 2022 ). Another example, TRAF3IP2-AS1, is the antisense lncRNA of the gene encoding for Act1 ( TRAF3IP2 ) and negatively regulates IL-17 signal by downregulating the transcription factor essential for Act1 expression ( He et al, 2021 ).…”