Abstract
Bone marrow-derived circulating monocytes contribute to the replenishment and maintenance of the intestinal macrophage population. Intestinal monocytes undergo context-dependent phenotypic and functional adaptations to either maintain local immune balance or support intestinal inflammation. Here we use monocyte adoptive transfer to dissect the dynamics of monocyte-to-macrophage differentiation in normal and inflamed small intestine. We find that during homeostasis CCR2 and β7-integrin mediate constitutive homing of monocytes to the gut. By contrast, intestinal inflammation increases monocyte recruitment via CCR2, but not β7-integrin. In the non-inflamed intestine, monocytes gradually differentiate to express genes typically associated with tolerogenic macrophage functions. Conversely, immediately upon entry into the inflamed intestine, monocytes adapt a different expression pattern in a partly Trem-1-dependent manner. Our observations suggest that inflammation fundamentally changes the kinetics and modalities of monocyte differentiation in tissues.
Highlights
Bone marrow-derived circulating monocytes contribute to the replenishment and maintenance of the intestinal macrophage population
Monocyte differentiation has been suggested to progress through distinct phenotypic developmental stages referred to as the ‘’monocyte waterfall”: incoming monocytes are Ly6C+MHCII− cells differentiating via Ly6C+ MHCII+ intermediates into Ly6C−MHCII+ macrophages that eventually gain high expression of CX3CR1, characteristic of the macrophages in the normal adult gut lamina propria[11,22]
Lamina propria cells were isolated from small intestine and adoptively transferred cells were identified by the expression of congenic markers
Summary
Bone marrow-derived circulating monocytes contribute to the replenishment and maintenance of the intestinal macrophage population. In contrast to macrophages abundantly present in homeostasis, the CX3CR1int population abundantly produces inflammatory mediators such as TNF, IL-1, IL-6, and CCL210–13 These proinflammatory monocytes/macrophages derive from the influx of circulating monocytes and exacerbate the inflammation. Both CCR2 and β7-integrin deficiency have been reported to ameliorate experimental colitis by reducing the monocyte trafficking to the inflamed colon[23,24,25]. Ablation of circulating monocytes by anti-CCR2 antibodies prevented severe colitis[12] This suggests that the magnitude of monocyte recruitment and their subsequent local differentiation in the tissue are key determinants regulating homeostasis and inflammation in the gut. The mechanisms that allow for such context-dependent outcomes have not been fully defined
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