AMPK suppresses Th2 cell responses by repressing mTORC2.

Pandit, Mahesh; Timilshina, Maheshwor; Gu, Ye; Acharya, Suman; Chung, Yeonseok; Seo, Sang-Uk; Chang, Jae-Hoon

Allergic inflammation is a T helper 2 (Th2) cell-driven pathophysiological phenomenon, but the mechanism by which the metabolic cascade affects Th2 cell differentiation remains unclear. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) and intracellular energy sensors in Th2 cell differentiation and the pathogenesis of allergic inflammation. Accordingly, T-cell-specific AMPK or Sirtuin 1 (Sirt1)-knockout mice were subjected to allergic inflammation, and their Th2 cell responses were investigated. The results demonstrated that inducing allergic inflammation in AMPK- and Sirt1-knockout mice increased Th2 cell responses and exacerbated allergic phenotypes. Furthermore, treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, ameliorated allergic inflammation in mice. Mechanistically, our findings revealed that AMPK repressed mechanistic target of rapamycin complex 2 (mTORC2), which downregulated the expression of suppressor of cytokine signaling 5 (SOCS5) in CD4 T cells. In addition, the loss of AMPK signaling reduced SOCS5 expression and increased interleukin-4-STAT6–GATA3 axis-mediated Th2 cell differentiation. Finally, the T-cell-specific deletion of Rictor, a member of mTORC2, in Sirt1T-KO mice led to the reversal of allergic exacerbation to the level in control mice. Overall, our findings suggest that AMPK in CD4 T cells inhibits the differentiation of Th2 cells by repressing mTORC2 and thus serves as a potential target for Th2 cell-associated diseases. Allergic inflammation: When T-helper cells aren't helping Boosting activity of an energy-regulating enzyme helps reduce the severity of allergic inflammation driven by T-helper 2 (Th2) immune system cells. In allergic inflammation, the body overreacts to an allergen, and too many Th2 cells are activated. Although some of the molecules involved are known, the details are not well understood. Researchers from South Korea led by Jae-Hoon Chang at Yeungnam University, Gyeongsan, and Sang-Uk Seo at The Catholic University of Korea, Seoul, investigated how the AMPK enzyme, known to regulate T cells in response to cellular energy levels, affects Th2 cell differentiation. Mice lacking AMPK had increased numbers of Th2 cells and prone to allergic inflammation. Administering a drug that boosts AMPK fully alleviated allergy symptoms in mice. Improving our understanding of how Th2 cells are activated may help in finding better treatments for allergic inflammation.

Experimental & Molecular Medicine EMM, 2022, Vol 54, Issue 8, p1214

1226-3613

Academic Journal

10.1038/s12276-022-00832-x