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English: Figure 2. Heterogeneity, origin and differentiation of intestinal macrophages. The majority of mucosal macrophages are replenished by classical monocytes that enter the mucosa in a CCR2-dependent manner and differentiate through a series of intermediaries (mouse-and human-specific markers denoted in blue and green, respectively) to give rise to mature macrophages, which can be identified in both mouse and man as CD64+MHCIIhi CD206+CD163+ cells (common markers denoted in red). In addition, high levels of CD11b, CD11c, CD14, and CX3CR1 are characteristic features of murine LP macrophages. In contrast, human LP macrophages express only low levels of most of these markers but express high levels of CD209. Once in the mucosa and under cues from the local environment, monocytes first upregulate MHCII and downregulate molecules involved in extravasation, such as CCR2, LFA-1 and CD62L. They then upregulate phagocytic receptors and increase their production of anti-inflammatory cytokines, as well as becoming hyporesponsive to stimulation through e.g., TLRs. Studies in mice have identified IL10, TGFβ, and CX3CL1 as key factors in promoting macrophage differentiation in the healthy mucosa. Furthermore, exposure to the microbiota and its metabolites is known to influence macrophage differentiation and the rate of their turnover in the LP. Mature macrophages may also regulate their own turnover through secretion of monocyte chemoattractants, such as CCL2, CCL7, CCL8, and CCL12. Longer-lived macrophages may also exist in the murine intestinal mucosa and submucosa, and can be identified by their expression of the phagocytic receptor Tim4. While sharing certain features with their LP counterparts, such as CD64, MHCII, CD206, and CD163 expression, muscularis macrophages have a relatively distinct phenotype. In mouse, they express low levels of CD11c but high levels of the immunoregulatory cytokine RELMα, whereas in man, they have high levels of CD14 and CD11b. Muscularis macrophages are acutely dependent on CSF1 and norepinephrine signaling by sympathetic neurons via β2 adrenergic receptors (β2AR) shapes their differentiation. Monocytes also replenish macrophages of the muscularis, although the rate of replenishment is slower than in the mucosa and a larger proportion of these macrophages are long-lived.