Loss of miR-29a/b1 promotes inflammation and fibrosis in acute pancreatitis
Shatovisha Dey, Lata M. Udari, Primavera RiveraHernandez, Jason J. Kwon, Brandon Willis, Jeffrey J. Easler, Evan L. Fogel, Stephen Pandol, Janaiah Kota
Shatovisha Dey, Lata M. Udari, Primavera RiveraHernandez, Jason J. Kwon, Brandon Willis, Jeffrey J. Easler, Evan L. Fogel, Stephen Pandol, Janaiah Kota
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Research Article Gastroenterology Genetics

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

Abstract

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 TGFβ1 coupled with persistent αSMA+ 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.

Authors

Shatovisha Dey, Lata M. Udari, Primavera RiveraHernandez, Jason J. Kwon, Brandon Willis, Jeffrey J. Easler, Evan L. Fogel, Stephen Pandol, Janaiah Kota

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Figure 10

miR-29a/b1–KO exhibits systemic effects in caerulein-induced AP.

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miR-29a/b1–KO exhibits systemic effects in caerulein-induced AP. (A) Cir...
(A) Circulating serum IL-6 levels were measured in saline- (Cer–) or caerulein-treated WT and miR-29a/b1–KO mice by ELISA (n = 3 mice/group/time point). (B) MPO activity in lung homogenates of saline- (Cer–) or caerulein-treated WT and miR-29a/b1–KO mice at the indicated time points (n = 5/group/time point). (C) Representative images for H&E staining in the lungs of saline- (Cer–) or caerulein-dosed WT and KO mice at the indicated time points. Scale bars: 200 μm. (D) Tissue/air-space ratio in the lung of saline- (Cer–) or caerulein-dosed WT and KO mice at the given time points (n = 3 animals/group/time point). (E) Representative images for Masson’s trichrome staining in the lungs of saline- (Cer–) or caerulein-dosed WT and KO mice at the indicated time points. Scale bars: 200 μm. (F) Fibrosis from Masson’s trichome staining was scored based on 5 high-powered fields. (G) Representative images for F4/80 staining in the lungs of saline- (Cer–) or caerulein-dosed WT and KO mice at the indicated time points. Scale bars: 50 μm. (H) F4/80+ macrophages were quantified in the lungs of WT and KO mice and represented as percentage of positive cells. IHC images and quantifications represent n = 3 animals/group/time point. Results in graph represent mean ± SEM. Asterisk denotes difference with saline-treated WT mice; # symbol denotes difference between caerulein dosed WT and miR-29a–KO mice at a given time point; *P < 0.05, #P < 0.05, **P < 0.01, and ##P < 0.01, 2-way ANOVA with Šídák post hoc test.