Dynamics of Colon Monocyte and Macrophage Activation During Colitis

Abstract

Background: Macrophages are pivotal in coordinating a range of important processes in the intestines, including controlling intracellular infections and limiting damaging inflammation against the microbiota. However, it is not clear how gut macrophages, relative to recruited blood monocytes and other myeloid cells, contribute to the intestinal inflammatory milieu, nor how macrophages and their monocyte precursors mediate recruitment of other immune cells to the inflamed intestine.Methods: Myeloid cell populations isolated from colonic inflammatory bowel disease (IBD) or murine dextran sulphate sodium (DSS) induced colitis were assessed using flow cytometry and compared to healthy controls. In addition, mRNA expression profiles in human and murine colon samples, and in macrophages and monocytes from healthy and inflamed murine colons, were analysed by quantitative PCR (qPCR) and mRNA microarray.Results: We show that the monocyte:macrophage balance is disrupted in colon inflammation to favour recruitment of CD14+HLA-DRInt cells in humans, and Ly6CHi monocytes in mice. In addition, we identify that murine blood monocytes receive systemic signals enabling increased release of IL-1β prior to egress from the blood into the colon. Further, once within the colon and relative to other myeloid cells, monocytes represent the dominant local source of both IL-1β and TNF. Finally, our data reveal that, independent of inflammation, murine colon macrophages act as a major source of Ccl7 and Ccl8 chemokines that trigger further recruitment of their pro-inflammatory monocyte precursors.Conclusions: Our work suggests that strategies targeting macrophage-mediated monocyte recruitment may represent a promising approach for limiting the chronic inflammation that characterises IBD.

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

“…It is now clear that the frequency and number of Mfs among intestinal LP cells is increased in IBD patients compared to controls, especially in active lesion areas (132,221,223,225,226,228,246,263,(267)(268)(269)(270)(271)(272) (Figure 5E). More specifically, the augmentation of intestinal Mfs is due to an increase in the frequency of immature Mfs among LP cells, despite that somewhat different surface markers and combinations thereof have been used to characterized them (i.e., HLA-DR or CD11c levels; scRNA-seq) (132,221,223,225,226,228,256,263,270,(272)(273)(274)(275) (Figure 5F). This accumulation seems to be due to the inflammatory intestinal microenvironment of IBD patients, which boosts the recruitment of classical monocytes through mechanisms involving CCL2, IL-8, and TGF-β signaling (223,276).…”

Correlation between Serological Biomarkers and Disease Activity in Patients with Inflammatory Bowel Disease

“…In this study, as mentioned above, we accounted for the potential confounders by enrolling only the initially diagnosed IBD patients, and other leukocyte subtypes and ratios were examined. Monocytes, a subset of leukocytes, differentiate into macrophages and dendritic cells in the inflamed tissues, involving in innate immunity by releasing proinflammatory cytokines, chemokines, and pathogen-associated molecular patterns [30][31][32]. us, activation of monocytes is prospected to be initiated during the active phase of IBD.…”

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

“…An increase in myeloid monocytic cells in peripheral blood has been associated with some inflammatory pathologies [36]. In particular, CD11b+Ly6C hi (Ly6C hi ) monocytes increase in number during intestinal inflammation associated with tumor growth and invasiveness [37]. Figure 5A shows a significant increase of CD11b + Ly6C hi Ly6G − cells in the circulation of untreated CAC mice, but this monocytic population was diminished after the 5-FU, AS1517499, Trimethylglycine, and AS+5-FU therapies; whereas Trim+5-FU only displayed a discrete reduction of this cell population.…”