α7nAChR activation promotes the generation of Treg cells by enhancing the dephosphorylation of Foxo1 via the IP3R/Ca2+/calcineurin pathway

While it is well documented that acetylcholine released through vagus nerve stimulation can enhance the differentiation of regulatory T cells (Treg cells) and alleviate symptoms of multiple autoimmune diseases by targeting the α7 nicotinic acetylcholine receptor (α7nAChR), the underlying mechanisms remain elusive. Here, we show that α7nAChR activation by agonists promoted Treg cell differentiation in vitro. Mechanistically, α7nAChR facilitates the recruitment of forkhead box O1 (FOXO1) to the forkhead box P3 (Foxp3) promoter by enhancing Calcineurin activity, which increases the dephosphorylation of FOXO1 at Ser319. Moreover, α7nAChR activation augments Calcineurin activity through the activation of the inositol 1,4,5-trisphosphate receptor (IP3R), which in turn facilitates calcium ion release from the endoplasmic reticulum. The promotion of α7nAChR on the generation of Treg cells in the spleens, mesenteric lymph nodes and lamina propria of colon mucosa in colitis mice is nearly completely reversed by pretreatment of either AAV-shα7nAChR or AAV-shIP3R. In summary, α7nAChR promotes the generation of Treg cells by recruiting FOXO1 to the Foxp3 promoter via the IP3R/Ca2+/Calcineurin pathway, and α7nAChR and IP3R may serve as promising therapeutic targets for Treg cell deficiency-related diseases.

Calcineurin; Foxo1; IP3R; Treg cells; α7nAChR.