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

• Published in: Molecular therapy Vol. 30; no. 4; pp. 1754 - 1774
• Main Authors: Du, Wenya, Liu, Geng, Shi, Na, Tang, Dongmei, Ferdek, Pawel E., Jakubowska, Monika A., Liu, Shiyu, Zhu, Xinyue, Zhang, Jiayu, Yao, Linbo, Sang, Xiongbo, Zou, Sailan, Liu, Tingting, Mukherjee, Rajarshi, Criddle, David N., Zheng, Xiaofeng, Xia, Qing, Berggren, Per-Olof, Huang, Wendong, Sutton, Robert, Tian, Yan, Huang, Wei, Fu, Xianghui
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 06-04-2022; American Society of Gene & Cell Therapy
• Subjects: autophagy; endoplasmic reticulum stress; inflammation; Medicin och hälsovetenskap; mouse models; noncoding RNA; Original; pancreatic acinar cell; store-operated calcium entry channels; targeted therapy; transient receptor potential canonical channels; pancreatic acinar cell; mouse models; targeted therapy; noncoding RNA; autophagy; transient receptor potential canonical channels; inflammation; store-operated calcium entry channels; endoplasmic reticulum stress
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2022.01.033

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.
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Du and colleagues identified microRNA-26a as a crucial checkpoint for calcium overload in pancreatic acinar cells, the central event that induces acute pancreatitis, a common digestive disease without specific treatment, providing a previously unknown mechanism underlying acute pancreatitis pathogenesis and a novel therapeutic option for this disease.