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PRKAR2A deficiency protects mice from experimental colitis by increasing IFN-stimulated gene expression and modulating the intestinal microbiota
Mucosal Immunology ( IF 7.9 ) Pub Date : 2021-08-04 , DOI: 10.1038/s41385-021-00426-2
Lumin Wei 1 , Rongjing Zhang 2 , Jinzhao Zhang 2 , Juanjuan Li 1 , Deping Kong 2 , Qi Wang 1 , Jing Fang 3 , Lifu Wang 1
Affiliation  

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.



中文翻译:

PRKAR2A 缺陷通过增加 IFN 刺激的基因表达和调节肠道微生物群来保护小鼠免受实验性结肠炎

蛋白激酶 A (PKA) 通过其催化亚基在调节炎症中发挥重要作用。最近,据报道 PKA 调节亚基可直接调节一些信号通路并减轻炎症。然而,PKA 调节亚基在结肠炎症中的作用仍不清楚。因此,我们进行了这项研究,以研究 PKA 调节亚基 PRKAR2A 在结肠炎中的作用。我们观察到 PRKAR2A 缺陷保护小鼠免受葡聚糖硫酸钠 (DSS) 诱导的实验性结肠炎。我们的实验表明,Prkar2a的肠上皮细胞特异性缺失有助于这种保护。从机制上讲, Prkar2a中 PRKAR2A 的丢失-/-小鼠导致 IFN 刺激基因 (ISG) 表达增加和肠道菌群改变。ISG 的抑制部分逆转了Prkar2a -/-小鼠对 DSS 诱导的结肠炎的保护作用。抗生素治疗和交叉培养实验表明,Prkar2a -/-小鼠对 DSS 诱导的结肠炎的保护在很大程度上取决于肠道菌群。总而言之,我们的工作证明了 PRKAR2A 在促进 DSS 诱导的结肠炎方面的先前未识别的功能。

更新日期:2021-08-04
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