Blocking a Chemical Modification May Help Halt Inflammation in MS, Mouse Study Suggests

Blocking a Chemical Modification May Help Halt Inflammation in MS, Mouse Study Suggests

The pro-inflammatory protein interleukin-17 (IL-17) drives inflammation by promoting a chemical modification, called phosphorylation, in the RNA molecule of the regnase-1 enzyme, a mouse study shows.

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.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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