Choline acetyltransferase attenuates inflammation in a murine model of DSS colitis and sepsis

Abstract

Abstract Excessive immune cell activation and cytokine release leading to inflammatory conditions are associated with bidirectional immune system-brain communication and other physiological responses. The vagus nerve conveys sensory information to the brain and brain derived immunoregulatory signals suppressing peripheral cytokine levels and inflammation. Acetylcholine (A mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of choline acetyl transferase (ChAT), enzyme that catalyzes biosynthesis of acetylcholine, is unexplored. We studied the administration of ChAT in endotoxemia, sepsis and DSS colitis models. Intraperitoneal administration of ChAT significantly (p=0.002) suppresses serum levels of TNF (ChAT 1062.0pg/mL ± 113.0 vs vehicle 1711.0pg/mL ± 210.2) during murine endotoxemia. In a murine CLP sepsis model, administration of pegylated ChAT (PEG-ChAT) significantly improves survival (p=0.015), with a 55.6% survival in PEG-ChAT treated mice compared to a 22.2% survival in vehicle mice. In a preclinical model of inflammatory bowel disease, ChAT administration significantly improves body weight gain (d14 p=0.01 ChAT mice -5.1%±1.1 vs vehicle mice -15.5%±2.9), disease score (d11 p=0.006 ChAT mice 0.17DAI±0.05, vs vehicle mice 0.66DAI±0.13), and colon length (p=0.006 ChAT mice 7.15cm±0.2 vs vehicle mice 6.2cm±0.2) compared to vehicle. These results indicate that administration of ChAT inhibits TNF levels in acute endotoxemia and attenuates disease severity in murine models of sepsis and DSS-induced colitis, suggesting that further study of ChAT as an experimental anti-inflammatory therapeutic is warranted. Supported by grant from NIH to KJT and SSC.