Abnormally Differentiated Subsets of Intestinal Macrophage Play a Key Role in Th1-Dominant Chronic Colitis through Excess Production of IL-12 and IL-23 in Response to Bacteria

Abstract

Disorders in enteric bacteria recognition by intestinal macrophages (Mφ) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of Mφ in intestinal inflammation by using an IL-10-deficient (IL-10−/−) mouse colitis model. GM-CSF-induced bone marrow-derived Mφ (GM-Mφ) and M-CSF-induced bone marrow-derived Mφ (M-Mφ) were generated from bone marrow CD11b+ cells. M-Mφ from IL-10−/− mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-Mφ from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-Mφ was not significantly different between WT and IL-10−/− mice. In ex vivo experiments, cytokine production ability of colonic lamina propria Mφ (CLPMφ) but not splenic Mφ from WT mice was similar to that of M-Mφ, and CLPMφ but not splenic Mφ from IL-10−/− mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-Mφ from IL-10−/− mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPMφ and M-Mφ act as anti-inflammatory Mφ and suppress excess inflammation induced by bacteria in WT mice. In IL-10−/− mice, however, such Mφ subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal Mφ may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal Mφ to gut flora relationship in the development of colitis in IL-10−/− mice.

Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

“…EGFP-positive lymphocytes and DC, as well as neutrophils and macrophages, are likely to be a driving force in bacteria-induced colitis in IL-10 Ϫ/Ϫ mice (24,53,54). For example, IL-23 secreted by APC such as DC plays a critical role in supporting the development of T lymphocytes producing IL-17 (ThIL-17), an essential step for the development of colitis in IL-10 Ϫ/Ϫ mice (23).…”

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

“…Similarly, IL-10 −/− mice spontaneously develop colitis as a consequence of the preferential macrophage differentiation into proinflammatory subsets that produce large amounts of IL-12 and IL-23. Remarkably, the depletion of macrophages in these IL-10 −/− mice prevents the development of colitis [56].…”

“…These adaptations efficiently contribute to limiting the dissemination of luminal bacteria to the local mucosa and are also a prerequisite for the tight regulation of the immune responses of the adaptive immune system in the intestinal mucosa. As a further illustration of such a perfect functional adaptation, murine colonic macrophages become triggered to produce large amounts of IL-10 after encountering whole commensal bacteria [56]. …”

Monocyte Chemoattractant Protein-1 Contributes to Gut Homeostasis and Intestinal Inflammation by Composition of IL-10–Producing Regulatory Macrophage Subset

“…In contrast to splenic macrophages, recent studies have revealed that murine intestinal macrophages express several anti-inflammatory molecules, including IL-10, and induce differentiation of Foxp3 + T regulatory cells (Tregs) that are dependent on IL-10 and retinoic acid. Moreover, such intestinal macrophages suppress the intestinal dendritic cell-derived Th1 and Th17 immunity, which is dependent on or independent of Treg induction (7,8). Thus, recent studies have suggested that macrophages located in the intestinal mucosa play important roles in the maintenance of intestinal homeostasis by protecting the host from foreign pathogens and negatively regulating excess immune responses to commensals (9).…”

“…Because the intestinal mucosa is always exposed to numerous commensal bacteria, it is thought that the gut may possess regulatory mechanisms that prevent excessive inflammatory responses against commensal bacteria. It has been reported previously that intestinal macrophages do not express innate response receptors (4,5), and although these cells retain their phagocytic and bactericidal functions, they do not produce proinflammatory cytokines in response to several inflammatory stimuli, including microbial components (6,7). In contrast to splenic macrophages, recent studies have revealed that murine intestinal macrophages express several anti-inflammatory molecules, including IL-10, and induce differentiation of Foxp3 + T regulatory cells (Tregs) that are dependent on IL-10 and retinoic acid.…”