PRKAR2A deficiency protects mice from experimental colitis by increasing IFN-stimulated gene expression and modulating the intestinal microbiota

Mucosal Immunol. 2021 Nov;14(6):1282-1294. doi: 10.1038/s41385-021-00426-2. Epub 2021 Aug 4.

Abstract

Protein kinase A (PKA) plays an important role in regulating inflammation via its catalytic subunits. Recently, PKA regulatory subunits have been reported to directly modulate some signaling pathways and alleviate inflammation. However, the role of PKA regulatory subunits in colonic inflammation remains unclear. Therefore, we conducted this study to investigate the role of the PKA regulatory subunit PRKAR2A in colitis. We observed that PRKAR2A deficiency protected mice from dextran sulfate sodium (DSS)-induced experimental colitis. Our experiments revealed that the intestinal epithelial cell-specific deletion of Prkar2a contributed to this protection. Mechanistically, the loss of PRKAR2A in Prkar2a-/- mice resulted in an increased IFN-stimulated gene (ISG) expression and altered gut microbiota. Inhibition of ISGs partially reversed the protective effects against DSS-induced colitis in Prkar2a-/- mice. Antibiotic treatment and cross-fostering experiments demonstrated that the protection against DSS-induced colitis in Prkar2a-/- mice was largely dependent on the gut microflora. Altogether, our work demonstrates a previously unidentified function of PRKAR2A in promoting DSS-induced colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / etiology*
  • Colitis / metabolism*
  • Colitis / pathology
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / deficiency*
  • Disease Models, Animal
  • Gastrointestinal Microbiome* / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Immunomodulation*
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism
  • Mice
  • Mice, Knockout
  • Signal Transduction

Substances

  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • Interferon Regulatory Factors
  • Prkar2a protein, mouse