Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

Abstract

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.

Keywords: Crohn’s disease; dendritic cell; inflammatory bowel disease; innate immune system; intestinal homeostasis; macrophage; neutrophil; ulcerative colitis.

Figure 1

In healthy intestine (left), damage to the intestinal barrier triggers the recruitment of neutrophils from the circulation to the inflamed tissue along a chemotactic gradient formed by cytokines (IL-1β, IL-6, TNF-α), chemokines (CCL8, CXCL10, MIP-2), and growth factors (GM-CSF, G-CSF). Neutrophil recruitment is also mediated by bacteria-derived molecules such as formyl-methionyl-leucyl-phenylalanine (fMLP) and short-chain fatty acids (SCFAs). The recruited neutrophils participate in the elimination of microorganisms through phagocytosis, degranulation, reactive oxygen species (ROS) generation, and the release of neutrophil extracellular traps (NETs). Once their functions are completed, neutrophils undergo apoptosis and efferocytosis, facilitating the resolution of inflammation, tissue repair, and a return to normal tissue homeostasis. The participation of neutrophils and NETs in IBD is a double-edged sword (right). Neutrophils cooperate in wound healing and the resolution of inflammation by releasing vascular endothelial growth factors (VEGFs) and lipid mediators (protectin D1, resolvin E1). These factors impede neutrophil recruitment and promote phagocytosis. NETs impede the spread of microorganisms by trapping them in an environment of microbicidal components and stimulate the healing of the intestinal mucosa. Neutrophils directly cause tissue damage by releasing neutrophil elastase, proteases (MMPs), pro-inflammatory cytokines (IL-8, TNF-α, IL-1β), leukotriene B4, and ROS. These factors provoke not only injury to the epithelial barrier, but also the recruitment of neutrophils and other immune cells to the inflamed tissue. Neutrophil recruitment is also promoted by the cytokines IL-1α, IL-17, IL-22, G-CSF, and GM-CSF. Lack of the IBD protective gene CARD9 in neutrophils enhances ROS generation. IL-8, TNF-α, and PAD4 (increased in UC patients) contribute to NET production. Accumulation of NETs in the colon is accompanied by the induction of tissue damage and inflammation, as NETs also boost TNF-α and IL-1β production. Part of the figure was generated by using pictures from Servier Medical Art.

Figure 2

Macrophages and dendritic cell in homeostasis and IBD. Macrophages and DCs play important roles in homeostasis and in the development of IBD by phagocytosing cellular debris, producing cytokines, regulating tissue repair, and interacting with other cells. In the intestine, monocyte-derived macrophages (MΦ) are more abundant than tissue-resident macrophages of embryonic origin. Both perform phagocytosis, produce cytokines, and interact with other cells. Upon weaning, bone marrow-derived monocytes egress from the circulation and extravasate into the tissue, where they undergo differentiation and maturation (downregulation of Ly6C, production of MHCII, and increased expression of CX3CR1). In homeostasis, tissue-resident macrophages in the muscularis externa interact with enteric and myenteric neurons controlling intestinal secretion and motility, while in the lamina propria, macrophages provide signals to intestinal stem cells that give rise to goblet cells, Paneth cells, and intestinal epithelial cells. These macrophages also modulate T cell activities and functions, via the secretion of IL-10 for Tregs and IL-1β for Th17 cells. In addition, they affect ILC3 cells through the production of IL-1α and IL-1β. The migration of antigen-loaded CX3CR1^high intestinal macrophages to mesenteric lymph nodes is impaired by intestinal microbiota, thus affecting antigen presentation to T cells and effectively sustaining tolerance towards commensal bacteria. On the other hand, XCR1⁺ DCs play a tolerogenic role upon recognizing commensal bacterial components, while CD103⁺ cDC2s seem to be important for initiating oral tolerance through their capacity to generate RA and IL-10. In IBD, large numbers of Ly6C^high inflammatory monocytes are recruited to the intestine in a CCR2-dependent manner, becoming pro-inflammatory effector cells. These inflammatory macrophages produce TNFα, IL-6, and iNOS, and directly cause the onset and development of fibrosis through a disproportionate accumulation of ECM. The intestinal microbiota is impaired during chronic colitis, and CX3CR1^high macrophages can change their habits and migrate to lymph nodes. CD103⁺ cDC numbers are significantly reduced in the inflamed and uninflamed intestine in IBD; however, activated DCs can release inflammatory cytokines, in addition to type I IFN produced by pDCs. All these phenomena contribute to a generalized inflammation. Part of the figure was generated by using pictures from Servier Medical Art.