Loss of miR-29a/b1 promotes inflammation and fibrosis in acute pancreatitis
Loss of miR-29a/b1 promotes inflammation and fibrosis in acute pancreatitis
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DOI：
10.1172/jci.insight.149539
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发表时间：
2021-10-08
期刊：
影响因子：
8
通讯作者：
Kota, Janaiah
中科院分区：
文献类型：
--
作者：
Dey, Shatovisha;Udari, Lata M.;Kota, Janaiah
MicroRNA-29 （miR-29）是人类疾病中纤维炎症过程的关键调节因子。在这项研究中，我们发现miR-29a在实验和人类慢性胰腺炎中降低，因此我们利用条件miR-29a/b1- ko小鼠模型来研究miR-29a/b1簇在急性胰腺炎（AP）中的调节作用。miR-29a/b1充足（WT）和缺乏（KO）小鼠给予超量蛋白诱导AP，并在不同时间点进行表征，利用一系列免疫组化和生化分析AP参数。在小蛋白诱导的WT小鼠中，miR-29a在损伤时仍然显著下调。尽管在早期AP中WT小鼠存在高炎症环境、纤维化和实质紊乱，但在恢复过程中胰腺完全恢复。miR-29a/b1-KO小鼠表现出明显更大的炎症、淋巴细胞浸润、巨噬细胞极化和ECM沉积，并持续到恢复晚期，伴有持续的实质破坏。胰腺纤维化的增加伴随着TGF β 1的增强，并伴有持续的α SMA+ PSC激活。此外，这些小鼠表现出更高的循环IL-6和肺实质炎症。总之，这些研究表明，miR-29a/b1簇的缺失会影响AP的纤维炎症机制，导致(a)加重发病机制和(b)延迟疾病恢复，提示该分子对AP具有保护作用。
MicroRNA-29 (miR-29) is a critical regulator of fibroinflammatory processes in human diseases. In this study, we found a decrease in miR-29a in experimental and human chronic pancreatitis, leading us to investigate the regulatory role of the miR-29a/b1 cluster in acute pancreatitis (AP) utilizing a conditional miR-29a/b1-KO mouse model. miR-29a/b1-sufficient (WT) and-deficient (KO) mice were administered supramaximal caerulein to induce AP and characterized at different time points, utilizing an array of IHC 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. 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 TGF beta 1 coupled with persistent alpha SMA+ PSC activation. Additionally, these mice exhibited higher circulating IL-6 and inflammation in lung parenchyma. Together, this collection of studies indicates that depletion of miR-29a/b1 cluster impacts the fibroinflammatory mechanisms of AP, resulting in (a) aggravated pathogenesis and (b) delayed recovery from the disease, suggesting a protective role of the molecule against AP.