Acetylcholine ameliorates colitis by promoting IL-10 secretion of monocytic myeloid-derived suppressor cells through the nAChR/ERK pathway

Abstract

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.

α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates DSS-induced intestinal colitis by improving intestinal mucosal barrier function

“…Some studies demonstrated that autonomic nerve imbalance might contribute to the inflammatory progression in colitis models (O’Mahony et al 2009 , Abraham and Medzhitov 2011 ; Bonaz et al 2021 ). Inflammatory cytokines could be modulated by neurotransmitters including acetylcholine (Ach) (Rueda Ruzafa et al 2021 , Zheng et al 2021 ). The impaired parasympathetic function was found in up to 35% UC patients and 48% of CD patients (Lindgren et al 1993 ; Straub et al 1997 ).…”

Metabolomics Profile in Acute Respiratory Distress Syndrome By Nuclear Magnetic Resonance Spectroscopy In Patients With Community-Acquired Pneumonia

“…Choline uptake is essential for phospholipid remodeling and maintaining mitochondrial function and integrity in metabolically challenged macrophages to make up for the energy cost of in ammatory cytokine production and bactericidal activity and maintaining membrane stability [42]. Choline therapy modulates immune in ammation and suppresses oxidative stress, eliciting various pharmacological effects in many diseases [44][45][46][47]. In our study, serum choline levels of the ARDS group and urine choline of the no-ARDS group were signi cantly increased after treatment.…”

Capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption by blocking TRPV4 channels in healthy and colitic mice

“…The colons of both groups were collected and their lengths were measured. The stool score was performed based on two parameters as described previously ( 18 , 59 ). The stool characteristic was scored as follows: normal (score 0), soft with well-formed pellets (score 1), very soft (score 2), diarrhea (score 3), and severe diarrhea (score 4).…”

“…The resected mice colon tissues were stained with H&E. The histological scoring was evaluated by two double-blinded pathologists and performed based on the severity of inflammation, crypt damage, and ulceration as described previously ( 18 , 59 ). The inflammation was scored as follows: rare inflammatory cells in the lamina propria (score 0), increased numbers of granulocytes in the lamina propria (score 1), confluence of inflammatory cells extending into the submucosa (score 2), and transmural extension of the inflammatory infiltrate (score 3).…”