Macrophages in intestinal homeostasis and inflammation

Abstract

The intestine contains the largest pool of macrophages in the body which are essential for maintaining mucosal homeostasis in the face of the microbiota and the constant need for epithelial renewal but are also important components of protective immunity and are involved in the pathology of inflammatory bowel disease (IBD). However, defining the biological roles of intestinal macrophages has been impeded by problems in defining the phenotype and origins of different populations of myeloid cells in the mucosa. Here, we discuss how multiple parameters can be used in combination to discriminate between functionally distinct myeloid cells and discuss the roles of macrophages during homeostasis and how these may change when inflammation ensues. We also discuss the evidence that intestinal macrophages do not fit the current paradigm that tissue-resident macrophages are derived from embryonic precursors that self-renew in situ, but require constant replenishment by blood monocytes. We describe our recent work demonstrating that classical monocytes constantly enter the intestinal mucosa and how the environment dictates their subsequent fate. We believe that understanding the factors that drive intestinal macrophage development in the steady state and how these may change in response to pathogens or inflammation could provide important insights into the treatment of IBD.

Keywords: homeostasis; inflammation; intestine; macrophages; monocytes.

Figure 1

Under steady state conditions, Ly6C^hi monocytes constitutively enter the intestinal mucosa and differentiate into mature CX3CR1^hi F4/80⁺ macrophages (mϕ) through a series of short-lived CX3CR1^int intermediaries. These CX3CR1^hi mϕ are positioned immediately beneath the epithelial barrier and contribute to its integrity by secreting PGE2 which stimulates proliferation of epithelial progenitors. This positioning coupled with their high phagocytic capacity means they are poised to capture and destroy any invading commensals or pathogens, as well as clearing apoptotic or senescent cells. They may also be able to directly sample the luminal contents by the extending processes between the cells of the intestinal epithelial barrier. CX3CR1^hi mϕ also produce interleukin-10 (IL-10) constitutively, which facilitates secondary expansion of regulatory T cells in the mucosa and may also condition newly arrived monocytes. Regulatory T cells may also contribute to the conditioning of newly extravasated monocytes through their production of TGFβ. When homeostasis is perturbed by inflammation or infection, Ly6C^hi monocytes and their CX3CR1^int derivatives accumulate in large numbers and display enhanced pro-inflammatory characteristics. They produce pro-inflammatory cytokines which may support the maintenance of other effector cells such as IFNγ producing and IFNγ⁺ IL-17 double producing T cells. They also orchestrate the recruitment of other innate effector cells such as eosinophils through secretion of inflammatory chemokines. Importantly, during inflammation, CX3CR1^hi mϕ retain their anti-inflammatory signature, e.g. IL-10 production. Elicited classical monocytes may also play a regulatory role by controlling the production of TNFα and ROS by neutrophils.