Petite but Potent

Dousing the flames of autoimmunity poses a mighty challenge, but one tiny RNA could act as a powerful fire hose. New work by Youcun Qian and his colleagues at the Shanghai Institute for Biological Sciences suggests that interleukin 17 (IL-17), a signaling molecule that contributes to a number of autoimmune diseases, curbs production of a microRNA (miRNA) that normally quashes manufacture of inflammatory proteins. The report appeared online 3 June in Nature Medicine. 

“This is one of the most impressive papers I’ve ever seen on miRNAs because of its thoroughness,” says Bruce Trapp, a neuroscientist at the Lerner Research Institute of the Cleveland Clinic in Ohio. “They did the right experiments to address very essential questions regarding the function” of this miRNA and its suppression by IL-17. Especially noteworthy, Trapp says, is that the work documents IL-17’s quantities and behavior in cells from inflammatory lesions in both mice and humans, in contrast to other miRNA studies that have focused primarily on peripheral blood cells. Studying cells from diseased sites could yield information about key troublesome molecular activities.

MicroRNAs are short stretches of RNA that serve regulatory functions. In the last dozen years, scientists have increasingly recognized that the small molecules play important roles during normal cellular functioning. They bind to complementary sequences in mRNAs, thus setting in motion a series of events that winds up tamping down gene expression. Qian and his colleagues measured the amounts of miRNAs from inflamed areas of humans and mice with autoimmune diseases—joints of people with rheumatoid arthritis, kidneys of people with lupus, and spinal cords of mice with EAE, a common model for MS (see “Animal Arsenal”)—and compared them to those of miRNAs from healthy controls. Of hundreds assessed, four were dysregulated in all of the autoimmune diseases studied, and one was affected more strongly than the others. Quantities of miR-23b, a miRNA previously shown to be involved in cancer development but never before implicated in autoimmune disease, were significantly smaller in cells from the inflammatory lesions compared to those from healthy controls.

Following up on hints that IL-17 quantities and miR-23b expression were inversely correlated, the researchers treated normal cells from the joints and kidneys with a panel of inflammatory cytokines; IL-17 reduced miR-23b production more strongly than did any of the other cytokines. To home in on potential connections between miR-23b and inflammation, the team sought genes whose activity miR-23b might govern. From a list of 356 predicted targets identified by a number of experimental techniques, Qian and colleagues chose three—called TAB1, TAB2, and IKK-α—for further study. These proteins were previously known to rev up inflammation, and the new work showed that their expression is subdued by miR-23b under normal conditions.

When the researchers generated mice with extra miR-23b and then induced EAE, clinical symptoms took longer than usual to set in and were atypically mild. The same held true for mice with collagen-induced arthritis (CIA), the rheumatoid arthritis model used in the study. Conversely, when the team thwarted miR-23b—as IL-17 does—CIA and a murine model of lupus worsened markedly. These results and others suggest that the miRNA soothes autoimmune symptoms, likely by quelling its proinflammatory targets.

“miR-23b is like a brake, putting a damper on a number of inflammatory molecules,” says Michael Racke, a neurologist at Ohio State University in Columbus. “By losing that brake [when IL-17 is present], disease becomes much more severe.” Because miRNAs do not perfectly match their targets, one miRNA can influence the production of multiple messages. Racke says he’s excited that the paper’s long list of miR-23b’s predicted targets includes many that promote inflammation. This observation and the results from mice with altered miR-23b activity provide hope that the findings point toward practical applications. A miR-23b-based therapeutic agent “could be a blockbuster” because the current work suggests that the miRNA tames inflammation in a number of disorders, Racke says.

It’s not clear, however, how well the findings will apply to MS. Although the work is outstanding in its scope and data quality, says Lawrence Steinman, a neuroimmunologist at Stanford School of Medicine, “the evidence that IL-17 drives MS is not as strong as it is for other autoimmune diseases. It is a bit of a stretch to say at this point that [the miR-23b finding] will be helpful in MS.” Alexandre Prat, a neuroimmunologist at the University of Montreal in Canada, agrees. “Collectively, data are converging on a role for IL-17 in MS,” he says, “but we still can’t prove that this is true.”

Qian says he plans to take a step toward probing this question—and whether miR-23b could serve as a therapeutic target for treating MS—by testing whether manipulating miRNA activity can calm EAE symptoms. In the meantime, the new findings will undoubtedly fuel interest in the flame-quenching molecule.

Key open questions

• Is miR-23b underactive in people with MS?
• Would miR-23b activation alleviate MS-associated inflammation? 
• Would miR-23b respond to pharmacological manipulation?

Image Credit

Thumbnail image on landing page. "Conserved structure of miR-33 microRNA precursor" (a different microRNA from miR-23b). Rfam database, public domain.