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

Abstract

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-10RαMdel) 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-10RαMdel 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-10RαMdel 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-10RαMdel 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.

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

“…Remarkably, another function of IL-10 is to inhibit nitric oxide synthesis in monocytes and macrophages, which in this case could be related with e global redox status modulation (Li et al 2014), an aspect that is consistent with our previous results of GSH status. Besides, it is known that interleukin IL-12 (p70) promotes the differentiation of the Th1 cells and the production of IL-2 and IFN-γ thereby supporting cellular immunity, while IL-12 (p40) acts as an antagonist of IL-12 p70 (Suzuki et al 2003;Alam et al 2010).…”

Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

“…Recently, it has been reported the inhibition of NO and reactive oxygen species (ROS) levels in a mouse carrying a selective deletion of IL-10Rα in macrophages, had less severe colitis than wild-type mice. These data suggest that the protective effect of IL-10 is mainly mediated through the down-regulation of NO and ROS production by macrophages [76] . Globally, these observations and others suggest that cytokines present in the mucosa of patients with IBD modulate the iNOS expression and activity in the colonic epithelium and could play a homeostatic or inflammatory role in gut inflammation through iNOS modulation.…”

Treatment of Uveitis by In Situ Administration of Ex Vivo–Activated Polyclonal Regulatory T Cells

“…We then tested the role of ROS because these molecules are pathogenic in uveitis (27,28) and because one of the pleiotropic immunoregulatory effects of IL-10 is to reduce ROS production by myeloid cells (29)(30)(31). Administration of N-acetylcysteine, a ROS scavenger, led to a significant reduction of clinical signs of uveitis, compared with nontreated mice (Fig.…”