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.
Highlights
Inflammatory bowel disease (IBD) is a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract, which mainly include Crohn’s disease and ulcerative colitis (UC)[1]
RESULTS p-PRKAR2A is downregulated in patients with UC and mice with dextran sulfate sodium (DSS)-induced colitis First, we evaluated two widely expressed Protein kinase A (PKA) regulatory subunits (PRKAR1A and PRKAR2A) in different mouse tissues
PRKAR2A was mainly expressed in the intestine, heart, liver, and lungs, whereas PRKAR1A was mainly expressed in the heart, spleen, and lungs (Fig. 1a), suggesting that PRKAR2A is the predominant PKA regulatory subunit in the intestine
Summary
Inflammatory bowel disease (IBD) is a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract, which mainly include Crohn’s disease and ulcerative colitis (UC)[1] Many factors such as genetic predisposition, epithelial barrier defects, dysregulated immune responses, and gut microbiota dysbiosis have been demonstrated to participate in the occurrence of IBD, its pathogenesis is still not fully understood[2]. PRKAR1A, PRKAR1B, PRKAR2A, and PRKAR2B, are present, and each is encoded by a separate gene[4,5]. PKA subunits have distinct expression patterns: PRKAR1A and PRKAR2A are ubiquitously expressed, while PRKAR1B and PRKAR2B are expressed principally in the brain and adipose tissues[6,7,8,9]
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