microRNA146a suppresses pancreatitis via cross-talk with NF-kB and ASC-containing inflammasomes

Acute pancreatitis (AP) is a potentially lethal pancreatic inflammatory disease with no effective therapeutic options. Here, we identify microRNA-146a (miR-146a) as a targetable potent negative regulator of pancreatic inflammatory responses and associated tissue damage. Genetic ablation of miR-146a in mice exacerbated cerulein-induced AP, evidenced by elevated inflammatory cell infiltrates and acinar cell death, the former associated with activated macrophage infiltrates and upregulation of cytokines (e.g. IL-1b) and chemokines (e.g. CXCL2). RNA-seq analysis on cerulein-treated mouse pancreas tissues indicated that miR-146a deficiency upregulated molecular pathways for intrinsic apoptosis, actin cytoskeleton organisation and inflammation, while gene networks for mitochondrial function and cellular respiration were downregulated. .