Acetylcholine ameliorates colitis by promoting IL-10 secretion of monocytic myeloid-derived suppressor cells through the nAChR/ERK pathway.
Wanwei ZhengHuan SongZhongguang LuoHao WuLin ChenYuedi WangHaoshu CuiYufei ZhangBangting WangWenshuai LiYao LiuJun ZhangYiwei ChuFeifei LuoJie LiuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
The alteration of the enteric nervous system (ENS) and its role in neuroimmune modulation remain obscure in the pathogenesis of inflammatory bowel diseases (IBDs). Here, by using the xCell tool and the latest immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs technique, we found severe pathological damage of the entire ENS and decreased expression of choline acetyltransferase (ChAT) in IBD patients. As a result, acetylcholine (ACh), a major neurotransmitter of the nervous system synthesized by ChAT, was greatly reduced in colon tissues of both IBD patients and colitis mice. Importantly, administration of ACh via enema remarkably ameliorated colitis, which was proved to be directly dependent on monocytic myeloid-derived suppressor cells (M-MDSCs). Furthermore, ACh was demonstrated to promote interleukin-10 secretion of M-MDSCs and suppress the inflammation through activating the nAChR/ERK pathway. The present data reveal that the cholinergic signaling pathway in the ENS is impaired during colitis and uncover an ACh-MDSCs neuroimmune regulatory pathway, which may offer promising therapeutic strategies for IBDs.
Keyphrases
- signaling pathway
- induced apoptosis
- end stage renal disease
- ejection fraction
- chronic kidney disease
- pi k akt
- oxidative stress
- ulcerative colitis
- cell cycle arrest
- gene expression
- poor prognosis
- cell proliferation
- skeletal muscle
- dna methylation
- photodynamic therapy
- big data
- patient reported outcomes
- genome wide
- single cell