Pancreatic ductal deletion of S100A9 alleviates acute pancreatitis by targeting VNN1-mediated ROS release to inhibit NLRP3 activation

Theranostics. 2021 Mar 4;11(9):4467-4482. doi: 10.7150/thno.54245. eCollection 2021.

Abstract

Recent studies have proven that the overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also duct cells, however, pancreatic duct contribution in acinar cells homeostasis is poorly known and the molecular mechanisms leading to acinar insult and acute pancreatitis (AP) are unclear. Our previous work also showed that S100A9 protein level was notably increased in AP rat pancreas through iTRAQ-based quantitative proteomic analysis. Therefore, we investigated the actions of injured duct cells on acinar cells and the S100A9-related effects and mechanisms underlying AP pathology in the present paper. Methods: In this study, we constructed S100A9 knockout (s100a9-/-) mice and an in vitro coculture system for pancreatic duct cells and acinar cells. Moreover, a variety of small molecular inhibitors of S100A9 were screened from ChemDiv through molecular docking and virtual screening methods. Results: We found that the upregulation of S100A9 induces cell injury and inflammatory response via NLRP3 activation by targeting VNN1-mediated ROS release; and loss of S100A9 decreases AP injury in vitro and in vivo. Moreover, molecular docking and mutant plasmid experiments proved that S100A9 has a direct interaction with VNN1 through the salt bridges formation of Lys57 and Glu92 residues in S100A9 protein. We further found that compounds C42H60N4O6 and C28H29F3N4O5S can significantly improve AP injury in vitro and in vivo through inhibiting S100A9-VNN1 interaction. Conclusions: Our study showed the important regulatory effect of S100A9 on pancreatic duct injury during AP and revealed that inhibition of the S100A9-VNN1 interaction may be a key therapeutic target for this disease.

Keywords: S100A9; VNN1; acinar cells; acute pancreatitis; duct cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / drug effects
  • Acinar Cells / metabolism
  • Amidohydrolases / metabolism*
  • Animals
  • Calgranulin B / metabolism*
  • Cell Line
  • GPI-Linked Proteins / metabolism
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Docking Simulation / methods
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Pancreatic Ducts / drug effects
  • Pancreatic Ducts / metabolism*
  • Pancreatitis / drug therapy
  • Pancreatitis / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Small Molecule Libraries / pharmacology

Substances

  • Calgranulin B
  • GPI-Linked Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Reactive Oxygen Species
  • S100A9 protein, human
  • Small Molecule Libraries
  • Amidohydrolases
  • pantetheinase