The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells.

Abstract

In both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), the C-C chemokine receptor 6 (CCR6) is critical for pathogenic T helper 17 (Th17) cell migration to the central nervous system (CNS). Whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how CCR6 expression is post-transcriptionally regulated in Th17 cells is unknown. Here, using RNA-binding protein HuR conditional knock-out (KO) and wild-type (WT) mice, we present evidence that HuR post-transcriptionally regulates CCR6 expression by binding to and stabilizing Ccr6 mRNA and by promoting CCR6 translation. We also found that HuR down-regulates several microRNA expressions, which could target the 3'-UTR of Ccr6 mRNA for decay. Accordingly, knock-out of HuR reduced CCR6 expression on Th17 cells and impaired their migration to CNS compared with the response of WT Th17 cells and thereby ameliorated EAE. Together, these findings highlight how HuR contributes to Th17 cell-mediated autoimmune neuroinflammation and support the notion that targeting HuR might be a potential therapeutic intervention for managing autoimmune disorders of the CNS.

• Authors: Jing Chen, Jennifer L Martindale, Carole Cramer, Myriam Gorospe, Ulus Atasoy, Paul D Drew, Shiguang Yu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 35 Pg. 14532-14543 (09 01 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28684423 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural)

Chemical References

• 3' Untranslated Regions
• CCR6 protein, mouse
• ELAV-Like Protein 1
• ELAVL1 protein, human
• Elavl1 protein, mouse
• MicroRNAs
• RNA, Messenger
• Receptors, CCR6

Topics

• 3' Untranslated Regions
• Animals
• Autoimmune Diseases of the Nervous System (immunology, metabolism, pathology)
• Cell Line
• Cell Movement
• Cells, Cultured
• Central Nervous System (immunology, metabolism, pathology)
• ELAV-Like Protein 1 (antagonists & inhibitors, genetics, metabolism)
• Encephalomyelitis (immunology, metabolism, pathology)
• Gene Expression Regulation
• Humans
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• MicroRNAs (metabolism)
• Protein Biosynthesis
• RNA Interference
• RNA Stability
• RNA, Messenger (metabolism)
• Receptors, CCR6 (agonists, antagonists & inhibitors, genetics, metabolism)
• T-Lymphocytes, Helper-Inducer (cytology, immunology, metabolism, pathology)