Inhibition of CHRM3 Alleviates Necrosis Via the MAPK-p38/miR-31-5p/RIP3 Axis in L-Arginine-Induced Severe Acute Pancreatitis

Pancreas. 2020 Nov/Dec;49(10):1335-1341. doi: 10.1097/MPA.0000000000001684.


Objectives: Pancreatic acinar necrosis is a typical feature in the early phase of severe acute pancreatitis (SAP). Muscarinic acetylcholine receptor M3 (CHRM3) has been reported to play important roles in promoting insulin secretion and tumor cell proliferation, but its effect on necrosis remains unknown. This study revealed the important role of CHRM3 in regulating L-arginine-induced SAP and the molecular mechanisms.

Methods: To verify the function of CHRM3, pancreatic tissues and primary acinar cells of CRISPR/Cas9-mediated Chrm3 knockout mice were used in CHRM3 knockdown experiments, and to ascertain the CHRM3 overexpression, PLV-EGFP-Chrm3 plasmids were transfected in acinar cells in vitro.

Results: In L-arginine-induced SAP, CHRM3 is activated and regulates SAP through the mitogen-activated protein kinase/p38 pathway. Moreover, the expression of miR-31-5p decreased in the SAP model both in vitro and in vivo. Mir-31-5p effects the necrosis of acinar cells in SAP by upregulating the target gene RIP3, and miR-31-5p is a downstream miRNA of CHRM3.

Conclusions: Necrosis in L-arginine-induced SAP is promoted by CHRM3 through the mitogen-activated protein kinase-p38/miR-31-5p/RIP3 axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / enzymology*
  • Acinar Cells / pathology
  • Animals
  • Arginine
  • Cells, Cultured
  • Disease Models, Animal
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Necrosis
  • Pancreas / enzymology*
  • Pancreas / pathology
  • Pancreatitis / chemically induced
  • Pancreatitis / enzymology
  • Pancreatitis / pathology
  • Pancreatitis / prevention & control*
  • Phosphorylation
  • Receptor, Muscarinic M3 / deficiency*
  • Receptor, Muscarinic M3 / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Chrm3 protein, mouse
  • MicroRNAs
  • Mirn31 microRNA, mouse
  • Receptor, Muscarinic M3
  • Arginine
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • p38 Mitogen-Activated Protein Kinases