A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

Wenya Du, Geng Liu, Na Shi, Dongmei Tang, Pawel E Ferdek, Monika A Jakubowska, Shiyu Liu, Xinyue Zhu, Jiayu Zhang, Linbo Yao, Xiongbo Sang, Sailan Zou, Tingting Liu, Rajarshi Mukherjee, David N Criddle, Xiaofeng Zheng, Qing Xia, Per-Olof Berggren, Wendong Huang, Robert SuttonYan Tian, Wei Huang, Xianghui Fu

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Abstract

Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca2+ ([Ca2+]i) overload; however, the underlying mechanisms in Ca2+ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca2+ entry (SOCE) channel expression, Ca2+ overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [Ca2+]i in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca2+]i overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [Ca2+]i overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca2+ signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.

Original languageEnglish
Pages (from-to)1754-1774
Number of pages21
JournalMolecular Therapy
Volume30
Issue number4
Early online date22 Jan 2022
DOIs
Publication statusPublished - 6 Apr 2022

Bibliographical note

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Funding Information:
Wei Huang has received research support and/or funding from Cypralis, Farsight, and Corvidia (all funds to the West China Hospital of Sichuan University). R.S. has received research support and/or funding from Calcimedica, Cypralis, GlaxoSmithKline, MSD/Merck, and Novartis; has been a consultant for AbbVie, Calcimedica, Cypralis, Eagle Pharmaceuticals, Novartis, and Takeda (all funds to the University of Liverpool); and is collaborating in the IMI2 TransBioLine project with multiple public and private institutions, including Janssen, Lilly, MSD/Merck, Novartis, Pfizer, Roche, and Sanofi-Aventis.

Funding Information:
We thank the staff from the Experimental Animal Center (Xiaoting Chen and Xijing Yang), Laboratory of Clinical Pathology (Li, Fei Chen, and Chunjuan Bao), and Core Research Facilities (Jie Zhang, Lin Bai, Zhen Yang, Jinkui Pi, Yu Ding, and Sisi Wu) of West China Hospital for their continuous support. This work was supported by the National Natural Science Foundation of China (81970561, 92157205, and 91540113 to X.F.; 82172986 to Y.T.; 81973632 to Wei Huang; 81774120 to Q.X.; 81800575 to T.L.; 82100682 to N.S.); the Ministry of Science and Technology (2018ZX09201018-005 to X.F.); the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC18049 to X.F.; ZYJC18005 to Q.X.); the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20191005 to X.F.); the China Postdoctoral Science Foundation (2019M660239 to N.S.); the National Cancer Institute (5R01CA139158 to Wendong Huang); the National Science Center of Poland (Narodowe Centrum Nauki [NCN], 2019/33/B/NZ3/02578 to P.E.F.); HOMING Program of the Foundation for Polish Science (Fundacja na rzecz Nauki Polskiej [FNP], HOMING/2017-4/31 to P.E.F.; HOMING/2017-3/23 to M.A.J.) co-financed by the European Union under the European Regional Development Fund; the UK National Institute for Health Research (NIHR) ICAT Award (R.M.); and the NIHR Senior Investigator Award (R.S.). X.F. Wei Huang, Y.T. R.S. and W.D. conceptualized and designed the experiments. X.F. Wei Huang, Y.T. and R.S. supervised the study. X.F. Wei Huang, T.Y. and Q.X. obtained funding. W.D. with the help of G.L. N.S. D.T. and S.L. carried out animal models and molecular biology experiments. P.E.F. M.A.J. and W.D. with help of L.Y. performed calcium measurements. D.T. S.L. Xinyue Zhu, X.S. S.Z. T.L. and Xiaofeng Zheng. were involved in certain parts of the experimental work. J.Z. provided SOM and heatmaps. N.S. and Q.X. provided human samples and clinical data. X.F. Wei Huang, Y.T. and R.S. wrote the manuscript. Wendong Huang provided critical mouse materials. R.M. D.N.C. and P.-O.B. critically revised the manuscript. All authors read and approved the final version of the manuscript. Wei Huang has received research support and/or funding from Cypralis, Farsight, and Corvidia (all funds to the West China Hospital of Sichuan University). R.S. has received research support and/or funding from Calcimedica, Cypralis, GlaxoSmithKline, MSD/Merck, and Novartis; has been a consultant for AbbVie, Calcimedica, Cypralis, Eagle Pharmaceuticals, Novartis, and Takeda (all funds to the University of Liverpool); and is collaborating in the IMI2 TransBioLine project with multiple public and private institutions, including Janssen, Lilly, MSD/Merck, Novartis, Pfizer, Roche, and Sanofi-Aventis.

Funding Information:
We thank the staff from the Experimental Animal Center (Xiaoting Chen and Xijing Yang), Laboratory of Clinical Pathology (Li, Fei Chen, and Chunjuan Bao), and Core Research Facilities (Jie Zhang, Lin Bai, Zhen Yang, Jinkui Pi, Yu Ding, and Sisi Wu) of West China Hospital for their continuous support. This work was supported by the National Natural Science Foundation of China ( 81970561 , 92157205 , and 91540113 to X.F.; 82172986 to Y.T.; 81973632 to Wei Huang; 81774120 to Q.X.; 81800575 to T.L.; 82100682 to N.S.); the Ministry of Science and Technology ( 2018ZX09201018-005 to X.F.); the 1.3.5 Project for Disciplines of Excellence , West China Hospital, Sichuan University ( ZYJC18049 to X.F.; ZYJC18005 to Q.X.); the National Clinical Research Center for Geriatrics , West China Hospital, Sichuan University ( Z20191005 to X.F.); the China Postdoctoral Science Foundation ( 2019M660239 to N.S.); the National Cancer Institute ( 5R01CA139158 to Wendong Huang); the National Science Center of Poland ( Narodowe Centrum Nauki [NCN], 2019/33/B/NZ3/02578 to P.E.F.); HOMING Program of the Foundation for Polish Science ( Fundacja na rzecz Nauki Polskiej [FNP], HOMING/2017-4/31 to P.E.F.; HOMING/2017-3/23 to M.A.J.) co-financed by the European Union under the European Regional Development Fund ; the UK National Institute for Health Research (NIHR) ICAT Award (R.M.); and the NIHR Senior Investigator Award (R.S.).

Publisher Copyright:
© 2022 The Authors

Keywords

  • autophagy
  • endoplasmic reticulum stress
  • inflammation
  • mouse models
  • noncoding RNA
  • pancreatic acinar cell
  • store-operated calcium entry channels
  • targeted therapy
  • transient receptor potential canonical channels

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