Origin, Differentiation, and Function of Intestinal Macrophages

Abstract

Macrophages are increasingly recognized as essential players in the maintenance of intestinal homeostasis and as key sentinels of the intestinal immune system. However, somewhat paradoxically, they are also implicated in chronic pathologies of the gastrointestinal tract, such as inflammatory bowel disease (IBD) and are therefore considered potential targets for novel therapies. In this review, we will discuss recent advances in our understanding of intestinal macrophage heterogeneity, their ontogeny and the potential factors that regulate their origin. We will describe how the local environment of the intestine imprints the phenotypic and functional identity of the macrophage compartment, and how this changes during intestinal inflammation and infection. Finally, we highlight key outstanding questions that should be the focus of future research.

Keywords: colitis; inflammation; intestine; macrophage; monocyte; ontogeny.

Figure 1

Homeostatic functions of intestinal macrophages. Intestinal lamina propria (LP) macrophages are highly phagocytic and are responsible for clearing apoptotic and senescent epithelial cells. Through their expression of tissue-remodeling metalloproteinases and secretion of factors that stimulate epithelial stem cell renewal, such as prostaglandin E2 (PGE2), hepatocyte growth factor (HGF) and Wnt ligands, they promote epithelial integrity. Their position under the epithelial monolayer and their bactericidal activity, mean LP macrophages are ideally placed to capture and destroy any bacteria that breach the barrier. They may also send cellular processes across the epithelial barrier to sample luminal contents. Macrophages can transfer acquired antigen to migratory dendritic cells (DCs) for presentation to T cells in the draining mesenteric lymph nodes. Through their production of immunoregulatory cytokines, such as IL10 and TGFβ, they maintain and facilitate secondary expansion of regulatory T cells (Tregs) locally in the LP. In a similar manner, they support Th17 cells and ILC3s through their production of IL1β, which is induced by exposure to the microbiota or its derivatives. Macrophages are also present in deeper layers of the gut wall, including the submucosa and muscularis externae. Submucosa macrophages are thought to support the integrity of the submucosal vasculature, although the factors involved in this interaction remain unclear. Muscularis macrophages participate in bidirectional crosstalk with sympathetic neurons of the enteric nervous system and influence gut motility.

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⁺MHCII^hi 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.