These findings support the development of therapeutics that block the phosphorylation of regnase-1 to halt IL-17-mediated inflammation, as seen in multiple sclerosis (MS), the researchers said.
The study, “Phosphorylation-dependent Regnase-1 release from the endoplasmic reticulum is critical in IL-17 response,” was published in the Journal of Experimental Medicine.
IL-17 is a signaling molecule that stimulates and mediates pro-inflammatory responses. Too much of IL-17 is one of the mechanisms underlying autoimmune disorders, like MS.
A protein known as regnase-1 normally acts to reduce the extent of inflammatory reactions.
Genes, or DNA sequences, are transcribed into molecules called RNA, which act as templates to make proteins. Regnase-1 works like chopping scissors, degrading RNA that codes for proteins associated with inflammation. This prevents their production and, as a consequence, halts inflammation.
A chemical modification, known as phosphorylation (the addition of a phosphate group), can inactivate regnase-1 action, leading to uncontrolled inflammation. Exactly how this modification occurs is unclear.
Now, a team led by researchers at the Osaka University in Japan, altered or deleted the modification sites of regnase-1 in mice, and analyzed how that impacted IL-17-mediated inflammation.
They first observed that the mutant mice resisted the induction of experimental autoimmune encephalomyelitis (EAE) — a similar condition to MS, characterized by demyelinating lesions associated with infiltrating immune cells.
Researchers found that stimulation with IL-17A caused regnase-1 phosphorylation. The protein was no longer able to bind to its targets, enhancing the stability of pro-inflammatory RNA molecules, and causing inflammation. Alteration or deletion of regnase-1 modification sites prevented IL-17-mediated inflammation.
“Using the mouse models, we showed that Regnase-1 is phosphorylated in response to IL-17 stimulation. The phosphorylated protein is expelled into the cytosol, where it can no longer interact with its target gene products,” Hiroki Tanaka, the study’s first author, said in a press release.
“Our model suggests that Regnase-1 is constitutively phosphorylated and inactivated in injured tissues of autoimmune patients, which are exposed to proinflammatory cytokines (e.g., members of the IL-1 family, as well as IL-17),” the researchers said.
Thus, the results indicate that IL-17-induced modification of regnase-1 triggers uncontrolled inflammation.
“Our results confirm that phosphorylation of Regnase-1 plays an important role in the regulation of various inflammatory responses,” said Shizuo Akira, the study’s senior author.”Based on these findings, we propose that Regnase-1 plays a critical role in the development of interleukin-17-mediated inflammatory diseases.”
“This is exciting because it means that we may be able to design therapeutic agents that block the phosphorylation of Regnase-1, which may prove effective in the treatment of interleukin-17-associated autoimmunity,” Akira concluded.
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