Intestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes

Abstract

Lamina propria (LP) macrophages are constantly exposed to commensal bacteria, and are refractory to those antigens in an interleukin (IL)-10-dependent fashion. However, the mechanisms that discriminate hazardous invasion by bacteria from peaceful co-existence with them remain elusive. Here we show that CD169+ macrophages reside not at the villus tip, but at the bottom-end of the LP microenvironment. Following mucosal injury, the CD169+ macrophages recruit inflammatory monocytes by secreting CCL8. Selective depletion of CD169+ macrophages or administration of neutralizing anti-CCL8 antibody ameliorates the symptoms of experimentally induced colitis in mice. Collectively, we identify an LP-resident macrophage subset that links mucosal damage and inflammatory monocyte recruitment. Our results suggest that CD169+ macrophage-derived CCL8 serves as an emergency alert for the collapse of barrier defence, and is a promising target for the suppression of mucosal injury.

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

“…[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.…”

“…The contributions of certain subpopulations of DC and macrophage lineages to the regulation of the development of acute colitis have been elucidated by utilizing Tg mouse lines endowed with the expression of DTR under the control of DCor macrophage-related genes, such as Itgax, 26 Cd169, 28,37 Clec4a4, 37 and Clec9a, 37 whereas the phenotype of Batf3 deficiency did not show any exacerbated inflammation during acute colitis. 38 Series of our studies have shown that pDCablated mice exhibited a near-complete and specific elimination of pDCs in the lymphoid tissues following DT treatment, but they retained other leukocytes, including cDC subsets.…”

“…27,28 We therefore compared the colonic production of CCR2 ligands between WT and pDCablated mice following DSS treatment. pDC-ablated mice exhibited the marked reduction of the transcriptional expressions of Ccl2, but not Ccl7 and Ccl8, in colon explants after oral administration of DSS than WT mice (Figure 7d).…”

“…[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.…”