Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors

Abstract

Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCIIhi, but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1int cells is present in resting colon and it expands during experimental colitis. Ly6ChiCCR2+ monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1int pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1hi mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

“…However, our data demonstrate an increased percentage of the Ly6C hi "inflammatory" monocyte population (P1 according to Bain et al (30)) in the lamina propria of pIC-and LPS-treated mice, which was not found in FO-fed animals or breastfed controls. This corresponds to other studies showing an increased number of inflammatory monocytes in the small bowel of mice submitted to the NEC protocol as well as in human NEC samples (31,32).…”

Maturation Phenotype of Peripheral Blood Monocyte/Macrophage After Stimulation with Lipopolysaccharides in Irritable Bowel Syndrome

“…Therefore, in line with the proposed cascade fashion development, it could be speculated that the presence of the different membrane markers found in the current study, suggests that there is a difference between patients with IBS and the controls in the monocyte/macrophage maturation process. In this sense, the CD11c, 17 CD206, 29 and CX3CR1 17 markers are not expressed in peripheral monocytes, but rather in a state of residence in the bowel, 17 which in our study is very likely associated with the cell-culture conditions. In the bowel, the macrophages express the CD11c 17 marker, although its presence is associated with differentiated macrophages.…”

“…28 Thus, analyzing a model of MNCs stimulated with LPS is a logical focus for speculating the possible response of these cells to bacterial stimuli and their comparison between IBS patients and controls. Likewise, it is important to point out that in the 2 studies using a murine model, Bain et al 29 and Tamoutounour et al 16 proposed that the conditions of the intestine lead to the development of the macrophage in a cascade-like fashion. This is a linear concept in which complete macrophage development up to a tolerant state is possible in a normal lamina propria, whereas an inflammatory state mainly promotes the maturation of proinflammatory response macrophages.…”

Dendritic Cells

“…Most of these cells are located deeper into the LP when compared to the network of phagocytic cells that is located right beneath the epithelial cells. These phagocytic cells express CD45, HLA-DR, CD14, CD64 and high levels of CX3CR1, and since these cells also do not migrate to the lymph nodes, they have been depicted as intestinal macrophages (Rivollier et al 2012 ;Bain et al 2012 ;Tamoutounour et al 2012 ;Mann et al 2013 ).…”