A microRNA checkpoint for Ca 2+ signaling and overload in acute pancreatitis
Wenya Du 1 , Geng Liu 1 , Na Shi 2 , Dongmei Tang 1 , Pawel E Ferdek 3 , Monika A Jakubowska 4 , Shiyu Liu 5 , Xinyue Zhu 1 , Jiayu Zhang 1 , Linbo Yao 5 , Xiongbo Sang 1 , Sailan Zou 1 , Tingting Liu 5 , Rajarshi Mukherjee 6 , David N Criddle 7 , Xiaofeng Zheng 8 , Qing Xia 5 , Per-Olof Berggren 9 , Wendong Huang 10 , Robert Sutton 11 , Yan Tian 12 , Wei Huang 13 , Xianghui Fu 14 Affiliations
- PMID: 35077860
- 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.
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.