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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
PRKAR2A deficiency protects mice from experimental colitis by increasing IFN-stimulated gene expression and
Lumin Wei1, Rongjing Zhang2, Jinzhao Zhang2
1Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Protein kinase A (PKA) regulatory subunit PRKAR2A promotes colitis. PRKAR2A deficiency protects mice from experimental colitis by altering gut microbiota and increasing IFN-stimulated genes.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Protein kinase A (PKA) regulates inflammation, primarily through its catalytic subunits.
- PKA regulatory subunits' role in colonic inflammation is largely unknown.
- Investigating PRKAR2A's function in colitis is crucial for understanding inflammatory pathways.
Purpose of the Study:
- To elucidate the role of the PKA regulatory subunit PRKAR2A in experimental colitis.
- To determine the mechanisms by which PRKAR2A influences colonic inflammation.
- To assess the impact of PRKAR2A deficiency on intestinal epithelial cells and gut microbiota.
Main Methods:
- Dextran sulfate sodium (DSS)-induced experimental colitis model in mice.
- Generation of mice with intestinal epithelial cell-specific deletion of Prkar2a.
- Analysis of IFN-stimulated gene (ISG) expression.
- Gut microbiota profiling and manipulation (antibiotic treatment, cross-fostering).
Main Results:
- PRKAR2A deficiency conferred significant protection against DSS-induced colitis.
- Intestinal epithelial cell-specific deletion of Prkar2a was responsible for the protective effect.
- Loss of PRKAR2A led to increased ISG expression and altered gut microbiota composition.
- Inhibition of ISGs partially abrogated the protective effect in PRKAR2A-deficient mice.
- Protection was largely dependent on the gut microflora, as shown by antibiotic and cross-fostering experiments.
Conclusions:
- PRKAR2A plays a previously unrecognized role in promoting DSS-induced colitis.
- PRKAR2A deficiency protects against colitis through mechanisms involving ISGs and gut microbiota.
- Targeting PRKAR2A or its downstream pathways may offer therapeutic strategies for colitis.
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