IL-10 modulates DSS-induced colitis through a macrophage – ROS – NO axis

Breakdown of the epithelial barrier due to toxins or other insults leads to severe colitis. IL-10 is a critical regulator of this, yet its cellular targets and mechanisms of action are not resolved. We address this here. Mice with a macrophage-selective deletion of IL-10Rα (IL-10Rα(Mdel)) developed markedly enhanced DSS-induced colitis that did not significantly differ from disease in IL-10(−/−) or IL-10Rα(−/−) mice; no impact of IL-10Rα-deficiency in other lineages was observed. IL-10Rα(Mdel) colitis was associated with increased mucosal barrier disruption in the setting of intact epithelial regeneration. Lamina propria macrophages did not show numerical or phenotypic differences from controls, or a competitive advantage over wild type cells. Pro-inflammatory cytokine production, and particularly TNF-α, was increased, though TNF-α neutralization failed to reveal a defining role for this cytokine in the aggravated disease. Rather, IL-10Rα(Mdel) lamina propria macrophages produced substantially greater levels of NO and ROS than controls. Inhibition of these had modest effects in wild type mice, though dramatically reduced colitis severity in IL-10Rα(Mdel) mice, and largely eliminated the differential effect of DSS in them. Therefore, IL-10’s palliative actions in DSS-induced colitis pre-dominantly results from its macrophage specific effects. Downregulation of NO and ROS production are central to IL-10’s protective actions.