The role of macrophages and dendritic cells in the initiation of inflammation in IBD

Abstract

In the healthy gastrointestinal tract, homeostasis is an active process that requires a careful balance of host responses to the enteric luminal contents. Intestinal macrophages and dendritic cells (DCs) comprise a unique group of tissue immune cells that are ideally situated at the interface of the host and the enteric luminal environment to appropriately respond to microbes and ingested stimuli. However, intrinsic defects in macrophage and DC function contribute to the pathogenesis of inflammatory bowel diseases, as highlighted by recent genome-wide association studies. Gastrointestinal macrophages and DCs participate in inflammatory bowel disease development through inappropriate responses to enteric microbial stimuli, inefficient clearance of microbes from host tissues, and impaired transition from appropriate proinflammatory responses to anti-inflammatory responses that promote resolution. By understanding how intestinal macrophages and DCs initiate chronic inflammation, new pathogenesis-based therapeutic strategies to treat human inflammatory bowel diseases will be elucidated.

Figure 1

LPMCs affect intestinal homeostasis in health and disease. LPMCs participate in maintaining intestinal homeostasis and in initiating disease when homeostasis is perturbed. (1) CD103–CX3CR1high LPMCs extend dendrites across the IEC barrier to sample luminal bacteria and antigens. (2) IECs and stromal cells produce local factors that condition LPMCs to be tolerant. (3) LP macrophages constitutively produce high levels of IL-10, which is necessary for the maintenance of Foxp3 expression in LP Tregs. (4) CD103+CX3CR1low LPDCs produce TGF-β and RA to induce Treg cells and imprint gut-homing receptors in adaptive immune cells. (5) CD103+CX3CR1low LPDCs induce IgA class switching in B cells. IgA is important in controlling the growth and composition of the enteric microbiota. (6) During perturbation of intestinal homeostasis, the enteric microbiota demonstrates dysbiosis. Additionally, the mucous layer just superficial to the IEC layer can break down, exposing IECs to the microbiota and inducing IECs to produce inflammatory cytokines. (7) Defects in intracellular bacterial clearance leads to persistent stimulation of LPMCs and induction of proinflammatory cytokines. IL-12 and IL-23 support the maintenance and differentiation of Th1 and Th17 cells, respectively. (8) CD103+CX3CR1low cells become inflammatory, producing increased amounts of IL-12, IL-6, IL-8, and TNF-α, supporting the differentiation of pathogenic T cells and the recruitment of inflammatory cells to the intestines.