Adenosine 2A receptor contributes to the facilitation of post-infectious irritable bowel syndrome by γδ T cells via the PKA/CREB/NF-κB signaling pathway

BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome (PI-IBS). ?d T cells play a crucial role in innate and adaptive immunity. Adenosine receptors expressed on the surface of ?d T cells participate in intestinal inflammation and immunity regulation.AIM To investigate the role of ?d T cell regulated by adenosine 2A receptor (A2AR) in PI-IBS.METHODS The PI-IBS mouse model has been established with Trichinella spiralis (T. spiralis) infection. The intestinal A2AR and A2AR in ?d T cells were detected by immunohistochemistry, and the inflammatory cytokines were measured by western blot. The role of A2AR on the isolated ?d T cells, including proliferation, apoptosis, and cytokine production, were evaluated in vitro. Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction (RT-PCR). The animals were administered with A2AR agonist, or A2AR antagonist. Besides, ?d T cells were also injected back into the animals, and the parameters described above were examined, as well as the clinical features. Furthermore, the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression (P < 0.05), and suppression of A2AR enhanced PI-IBS clinical characteristics, indicated by the abdominal withdrawal reflex and colon transportation test. PI-IBS was associated with an increase in intestinal T cells, and cytokine levels of interleukin-1 (IL-1), IL-6, IL-17A, and interferon-a (IFN-a). Also, ?d T cells expressed A2AR in vitro and generated IL-1, IL-6, IL-17A, and IFN-a, which can be controlled by A2AR agonist and antagonist. Mechanistic studies demonstrated that the A2AR antagonist improved the function of ?d T cells through the PKA/CREB/NF-?B signaling pathway.CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function of ?d T cells via the PKA/CREB/NF-?B signaling pathway.

Automated summary

This study found that γδ T cells play an important role in post-infectious irritable bowel syndrome (PI-IBS) through the regulation of adenosine 2A receptor (A2AR). The PI-IBS mouse model showed increased ATP content and A2AR expression, and inhibition of A2AR worsened the clinical characteristics of PI-IBS. In vitro and in vivo experiments revealed that γδ T cells express A2AR and produce IL-1, IL-6, IL-17A, and IFN-a in PI-IBS, which can be controlled by A2AR agonist and antagonist. Mechanistic studies demonstrated that A2AR antagonist improved the function of γδ T cells through the PKA/CREB/NF-κB signaling pathway.