MicroRNA Regulates Immune Response in Intestinal Inflammation

Results presented in a recently published paper revealed a previously unappreciated role for a specific microRNA in regulating the innate immune response during intestinal inflammation.

MicroRNAs (miRNAs) are a small noncoding family of 19- to 25-nucleotide RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer.

Investigators at the University of Colorado reported in the May 9, 2017, online edition of The Journal of Experimental Medicine that the microRNA miR-223 was increased in intestinal biopsies from patients with active inflammatory bowel disease (IBD) and in preclinical models of intestinal inflammation. The miR-223 miRNA is produced by neutrophils and monocytes and has previously been shown to repress the messenger RNA encoding the protein NLRP3, a key component of the inflammasome. Inflammasomes are molecular platforms activated by cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta (IL-1beta) to engage innate immune defenses.

To determine the ramifications of increased miR-223 in IBD, the investigators created model systems by genetically engineering lines of mice to lack the miRNA. They found that mice lacking miR-223 expressed higher levels of NLRP3, causing increased IL-1beta production and enhanced susceptibility to intestinal inflammation.

In contrast, the nanoparticle-mediated overexpression of miR-223 reduced the severity of experimental colitis, NLRP3 levels, and IL-1beta release.

"Our study highlights the miR-223-NLRP3-IL-1beta regulatory circuit as a critical component of intestinal inflammation," said senior author Dr. Eóin McNamee, assistant professor of gastroenterology, immunology, and physiology at the University of Colorado. "miR-223 serves to constrain the level of NLRP3 inflammasome activation and provides an early brake that limits excessive inflammation. Genetic or pharmacologic stabilization of miR-223 may hold promise as a future novel therapy for active flares in IBD."