Monocyte-derived mononuclear phagocytes, particularly macrophages, are crucial to maintain gastrointestinal homeostasis in the steady state but are also important for protection against certain pathogens. However, when uncontrolled, they can promote immunopathology. Broadly two subsets of macrophages can be considered to perform the vast array of functions to complete these complex tasks: resident macrophages that dominate in the healthy gut and inflammation-elicited (inflammatory) macrophages that derive from circulating monocytes infiltrating inflamed tissue. Here, we discuss the features of resident and inflammatory intestinal macrophages, complexities in identifying and defining these populations and the mechanisms involved in their differentiation. In particular, focus will be placed on describing their unique ontogeny as well as local gastrointestinal signals that instruct specialisation of resident macrophages in healthy tissue. We then explore the very different roles of inflammatory macrophages and describe new data suggesting that they may be educated not only by the gut microenvironment but also by signals they receive during development in the bone marrow. Given the high degree of plasticity of gut macrophages and their multifaceted roles in both healthy and inflamed tissue, understanding the mechanisms controlling their differentiation could inform development of improved therapies for inflammatory diseases such as inflammatory bowel disease (IBD).
Keywords: Commensal; Gastrointestinal; Inflammatory bowel disease; Macrophage; Monocyte; Mucosal.