Intestinal Macrophages in Resolving Inflammation

Abstract

Macrophages not only regulate intestinal homeostasis by recognizing pathogens to control enteric infections but also employ negative feedback mechanisms to prevent chronic inflammation. Hence, macrophages are intriguing targets for immune-mediated therapies, especially when barrier function in the gut is compromised to trigger aberrant inflammatory responses, most notably during inflammatory bowel diseases. Recently, there has been considerable progress in our understanding of human macrophage biology in different tissues, including the intestines. In this review, we discuss some new findings on the properties of distinct populations of intestinal macrophages, how resolution of inflammation and tissue repair by macrophages could be promoted by type 2 cytokines as well as other therapeutic interventions, and highlight some challenges for translating these findings into the future for this exciting area of immunology research.

Figure 1.

Orchestration of intestinal macrophages in homeostasis, inflammation and helminth infection. Macrophages residing in the lamina propria (LP) are strategically positioned in close proximity to the epithelial layer. CX₃CR1⁺ LP macrophages participate in sampling of luminal contents via extension of transepithelial dendrites and phagocytose transgressing pathogens. Through the secretion of immunoregulatory cytokines IL-10 and TGF𝛃, LP macrophages support the expansion of regulatory T cells (Tregs). Within the deeper layers of the gut wall, the submucosa and muscularis externa, macrophages engage in a reciprocal crosstalk with a network of enteric neurons. This molecular dialog is mediated by the secretion of bone morphogenic protein 2 (BMP2) by macrophages. In response, enteric neurons secrete CSF1 which further promotes BMP2 secretion. In the setting of intestinal inflammation and breach of the epithelial layer, proinflammatory macrophages are recruited and elicit a protective immune response mediated by the secretion of inflammatory cytokines IL-1𝛃, TNFα and IL-6. Helminth infection induces a type 2 immune response mediated by an induction of Tregs and Th2 cells. Enteric neurons may sense infection by helminths and produce the neuropeptide neuromedin U (NMU) that stimulates innate lymphoid type 2 cells (ILC2s) to produce type 2 cytokines that can alternatively activate intestinal macrophages.