Conventional dendritic cells regulate the outcome of colonic inflammation independently of T cells

Abstract

We explored the physiological role of conventional dendritic cells (cDCs) in acute colitis induced by a single cycle of dextran sodium sulfate administration. Depending on their mode of activation and independently of T cells, cDCs can enhance or attenuate the severity of dextran sodium sulfate-induced colitis. The latter beneficial effect was achieved, in part, by IFN-1 induced by Toll-like receptor 9-activated cDCs. IFN-1 inhibits colonic inflammation by regulating neutrophil and monocyte trafficking to the inflamed colon and restraining the inflammatory products of tissue macrophages. These data highlight a novel role of cDCs in the regulation of other innate immune cells and position them as major players in acute colonic inflammation.colitis ͉ Toll-like receptor 9 ͉ IFN-1

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

“…Similar to the published report, 26 cDC-ablated mice showed less symptom of acute colitis induced by a single cycle of DSS administration than WT mice, whereas there was no significant difference in the attenuation of the development of acute colitis between cDC-ablated and pDC-ablated mice (Supplementary Figure S1f,g). …”

“…[26][27][28] Notably, the deficiency of pDCs abrogates colonic inflammation and pathological symptom of acute colitis as well as infiltration of inflammatory leukocytes into inflamed colon in DSS-fed mice. We have previously shown that pDCs could be the primary inflammatory cells to produce cytokines upon recognition of appropriate endosomal TLR ligands and viral components for the induction of systemic inflammation.…”

“…Although the contributions of intestinal monocytes/macrophages and cDCs in the inflamed colon have been appreciated for the development of T-cell-independent acute colitis, [26][27][28] the mechanism responsible for the control of colonic inflammation and the function of distinct subsets of colitogenic phagocytes is still elusive. In this study, we revealed a critical function for pDCs in the induction of the mucosal inflammation that regulate the colonic accumulation of inflammatory phagocytes, leading to the initiation and aggravation of acute colitis.…”

“…Similar to IFN-I treatment of IBD patients with mixed results, in which a few of clinical studies initially reported promising results but most of these studies failed to demonstrate beneficial therapeutic effect or showed even exacerbations, 41 previous reports showed some controversies for the role of IFN-I signaling in the development of DSS-induced colitis when Ifnar1 À / À mice were used for the comparison of WT mice. 26,42,43 The reason why the IFN-I signaling has inconsistency for the control of DSS-induced acute colitis remains unclear, but the discrepancies might be explained by amount of oral application of DSS, 43 experimental conditions, and environmental factors. Taken together, these results suggest that pDCs regulate the colonic inflammation independent of their pathophysiological production of IFN-I.…”

“…[23][24][25] It has been shown that DSS-induced chronic colitis can be mediated by several subsets of intestinal innate phagocytic cells mobilized into the inflamed colon, such as monocytes/macrophages and cDCs, to sense pathogenassociated molecular patterns of the enteric bacterial flora and damage-associated molecular pattern molecules released from host dying cells through a variety of PRRs, and the occurrence of the intestinal pathogenesis is independently of T cells. [26][27][28] On the other hand, previous studies have shown the lack of peripheral blood pDCs in patients with active IBD, and instead their accumulation in the inflamed colonic mucosa and mesenteric lymph node (MLN) and dysfunction. 29,30 However, how pDCs contribute to the development of IBD remains unclear.…”