Depletion of Muscularis Macrophages Ameliorates Inflammation- driven Dysmotility in Murine Colitis Model

Abstract

Previously, the presence of a blood-myenteric plexus barrier and its disruption was reported in experimentally induced colitis via a macrophage-dependent process. The aim of this study is to reveal how myenteric barrier disruption and subsequent neuronal injury affects gut motility in vivo in a murine colitis model. We induced experimental colitis with dextran sulfate sodium (DSS), with the co-administration of liposome-encapsulated clodronate (L-clodronate) to deplete muscularis macrophages (MMs) in male mice. DSS-treated animals receiving concurrent L-clodronate injection showed significantly decreased MM-density compared to DSS-treated control (DSS-vehicle). DSS-clodronate-treated mice exhibited significantly slower whole gut transit time than DSS-vehicle-treated animals and comparable to that of controls. Experiments with oral gavage-fed Evans-blue dye show similar whole gut transit times in DSS-clodronate-treated mice as in control animals. Furthermore, qPCR-analysis on colon muscularis samples revealed that factors associated with neuroinflammation and neurodegeneration are overexpressed after DSS-treatment, but not in the case of concurrent L-clodronate administration. Our findings highlight that MM-infiltration in the muscularis layer is responsible for colitis-associated dysmotility and enteric neuronal dysfunction along with the release of mediators associated with neurodegeneration in a murine experimental model.