The impact of the TRPM2 ion channel on inflammation and macrophage metabolism in gastrointestinal models

Macrophages can play a vital role in regulating pro-inflammatory pathways that drive chronic inflammation and impact carcinogenesis. We previously published that TRPM2 regulates ROS production and the pro-inflammatory cytokine profile of macrophages in vivo and in vitro in H. pylori infection models. Since macrophage function and activation profiles can be regulated by metabolism, the impact of the TRPM2 channel on macrophage metabolism was assessed using bone marrow derived macrophages in Seahorse Extracellular Flux Assays and Mitotracker assays. The data demonstrated an unfavorable shift in mitochondrial content in Trpm2−/− macrophages after M1 activation. Consistent with this shift, the oxygen consumption rate was reduced in Trpm2−/− macrophages compared to WT macrophages, and the extracellular acidification rate at baseline and glycolytic reserve were higher in Trpm2−/− macrophages following classical activation. To investigate the role of TRPM2 in controlling other gastrointestinal pathologies, including acute colitis and carcinogenesis, the dextran sulfate sodium (DSS) colitis model and the azoxymethane (AOM)/DSS colitis-associated cancer (CAC) model were used. Trpm2−/− mice were not protected against acute DSS-induced colitis. Our endpoint analysis in the CAC model demonstrated that Trpm2−/− mice developed more numerous but smaller tumors than WT mice and immunohistological analysis suggests a shift in numbers of innate cells in the Trpm2−/− tumors compared to WT tumors. In the non-tumor areas, the histological injury score was reduced in the Trpm2−/− mice compared to WT mice. These data suggest that TRPM2 regulates Mϕ metabolism and impacts inflammation in the gastrointestinal tract.