A tiny molecule known as microRNA-142 plays a key role in the prevention of autoimmune responses through immune cells called regulatory T-cells (Tregs), according to a new study of mice.
These findings could enable new strategies to treat multiple sclerosis (MS) and other autoimmune diseases, the scientists said.
MicroRNAs (miRs) — tiny RNA molecules that regulate protein production — play a well-known role in the immune response, showing abnormal levels in cancer, and in rheumatoid arthritis and systemic lupus erythematosus, two autoimmune diseases.
Tregs are a subset of immune T-cells that dampen excessive immune responses. In humans, mutations in the FOXP3 gene — exclusively expressed in Tregs — cause widespread inflammation and autoimmunity. Mice with Treg-specific mutations in genes implicated in the production of miRs also develop autoimmunity. However, the specific miRs involved remain unknown.
miR-142-5p is the predominant form of mature miR-142 in Tregs, and is similar in mice and humans. Abnormally high levels of miR-142-5p have been shown in an experimental autoimmune encephalomyelitis (EAE) mouse model and in patients with MS, suggesting that miR-142 plays a role in the disease.
Using genetically altered mice, a team from King’s College London and University College London, in the U.K., found that miR-142 was the only miR associated with a “super enhancer” — a specific DNA region that tends to be associated to cell type-specific genes — in Tregs.
Genetically modified mice without miR-142 in Tregs developed inflammatory, lethal, and multisystem autoimmunity, although numbers of normal Tregs in the thymus, spleen, and peripheral lymph nodes were unaltered.
Animals with heterozygous mutations (meaning in only one of the two gene copies) in miR-142 were healthy up to at least 12 months, and their Tregs retained their normal activity. However, inflammation in liver, lungs and skin, as well as spleen enlargement indicated that normal levels of miR-142 are required for full suppressive function of Tregs.
Then, scientists observed that peripheral immune tolerance (the failure to mount an immune response) depended on the ability of miR-142-5p to suppress the production of inflammatory molecules called cytokines and the expression of the PDE3B gene, which codes for an enzyme called phosphodiesterase-3b. Through this suppression, miR-142-5p increases the levels of cAMP, a key cellular molecule in signaling pathways.
Subsequent experiments revealed that blocking PDE3B with a compound called cilostamide restored the suppressive function of Tregs. In mice without miR-142 in Tregs, treatment with cilostamide prevented autoimmune disease, which was associated with full restoration of the suppressive function of Tregs.
Furthermore, animals without both miR-142 in Tregs and PDE3B were healthy up to more than 20 weeks of age, with only mild organ inflammation and with restored Treg function, validating the hypothesis that increased PDE3B levels underlie Treg impairment.
“We therefore conclude that miR-142-5p represses PDE3B expression in Tregs and that this is essential for Treg suppressive function,” the researchers wrote. “In the absence of this critical molecular pathway, the mechanisms governing peripheral immune tolerance are compromised, resulting in a systemic lethal autoimmune syndrome,” they added.
“These findings represent a significant step forward in the understanding of the immune system and we believe many people worldwide may benefit,” Graham Lord, the study’s senior author now at The University of Manchester, said in a press release.
“We hope that this new discovery will lead to the development of new ways to treat autoimmunity, infectious diseases and cancer and we are incredibly excited about where this may lead,” Lord added.
Cilostazol, a PDE3 blocker, is already used in the treatment of intermittent claudication (pain caused by too little blood flow), but no current clinical trial is assessing PDE3 blockers in autoimmune diseases.
“In light of our findings, there is now a precedent for further investigation to establish whether modulation of PDE3B activity in Tregs may help to reestablish mechanisms of tolerance in patients suffering from autoimmune disease,” the team suggested.