miR-374a-5p regulates inflammatory genes and monocyte function in patients with inflammatory bowel disease

miR-374a-5p is a central regulator in IBD, as its down-regulation increases the expression of a module of key inflammatory mediators. miR-374a-5p up-regulation in vitro ameliorated the increased monocyte-driven inflammation by reducing proinflammatory mediators, migration capacity, and T cell activation. miR-374a-5p has a therapeutic potential in immune-mediated diseases. MicroRNAs are critical regulators of gene expression controlling cellular processes including inflammation. We explored their role in the pathogenesis of inflammatory bowel disease (IBD) and identified reduced expression of miR-374a-5p in IBD monocytes that correlated with a module of up-regulated genes related to the inflammatory response. Key proinflammatory module genes, including for example TNF alpha, IL1A, IL6, and OSM, were inversely correlated with miR-374a-5p and were validated in vitro. In colonic biopsies, miR-374a-5p was again reduced in expression and inversely correlated with the same inflammatory module, and its levels predicted subsequent response to anti-TNF therapy. Increased miR-374a-5p expression was shown to control macrophage-driven inflammation by suppressing proinflammatory mediators and to reduce the capacity of monocytes to migrate and activate T cells. Our findings suggest that miR-374a-5p reduction is a central driver of inflammation in IBD, and its therapeutic supplementation could reduce monocyte-driven inflammation in IBD or other immune-mediated diseases.