Loss of miR-29a/b1 promotes inflammation and fibrosis in acute pancreatitis.

MicroRNA-29 (miR-29) is a critical regulator of fibro-inflammatory processes in human diseases. In this study, we find a decrease in miR-29a in experimental and human chronic pancreatitis leading us to investigate the regulatory role of miR-29a/b1 cluster in acute pancreatitis (AP) utilizing a novel conditional miR-29a/b1 knockout (KO) mouse model. miR-29a/b1 sufficient (WT) and deficient (KO) mice were administered with supramaximal caerulein to induce AP and characterized at different timepoints, utilizing an array of immunohistochemical and biochemical analyses for AP parameters. In caerulein-induced WT mice, miR-29a remained dramatically downregulated at injury. Despite high inflammatory milieu, fibrosis and parenchymal disarray in the WT mice during early AP, the pancreata fully restored during recovery. Whereas miR-29a/b1 KO mice showed significantly greater inflammation, lymphocyte infiltration, macrophage polarization and ECM deposition, continuing until late recovery with persistent parenchymal disorganization. The increased pancreatic fibrosis was accompanied by enhanced TGFb1 coupled with persistent aSMA+ PSC activation. Additionally, these mice exhibited higher circulating IL6 and inflammation in lung parenchyma. Together, this collection of studies indicates that depletion of miR-29a/b1 cluster impacts the fibro-inflammatory mechanisms of AP resulting in (i) aggravated pathogenesis, and (ii) delayed recovery from the disease, suggesting a protective role of the molecule against AP.