Interactions between the host innate immune system and microbes in inflammatory bowel disease

Abstract

The intestinal immune system defends against pathogens and entry of excessive intestinal microbes; simultaneously, a state of immune tolerance to resident intestinal microbes must be maintained. Perturbation of this balance is associated with intestinal inflammation in various mouse models and is thought to predispose humans to inflammatory bowel disease (IBD). The innate immune system senses microbes; dendritic cells, macrophages, and epithelial cells produce an initial, rapid response. The immune system continuously monitors resident microbiota and utilizes constitutive antimicrobial mechanisms to maintain immune homeostasis. associations between IBD and genes that regulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), genes that control autophagy (eg, ATG16L1, IRGM), and genes in the interleukin-23-T helper cell 17 pathway indicate the important roles of host-microbe interactions in regulating intestinal immune homeostasis. There is increasing evidence that intestinal microbes influence host immune development, immune responses, and susceptibility to human diseases such as IBD, diabetes mellitus, and obesity. Conversely, host factors can affect microbes, which in turn modulate disease susceptibility. We review the cell populations and mechanisms that mediate interactions between host defense and tolerance and how the dysregulation of host-microbe interactions leads to intestinal inflammation and IBD.

Figure 1

Mechanisms of host defense and tolerance towards intestinal microbes. The intestinal environment modulates cellular differentiation in the immune system to control defense against pathogens and tolerance. (A) Defense mechanisms: Intestinal epithelial cells provide a physical barrier between the luminal microbes and the underlying intestinal tissues to control defense and tolerance. Specialized epithelial cells produce a mucus layer and secrete antimicrobial proteins that limit bacterial exposure to the epithelial cells. Production of large amounts of IgA provides additional protection from luminal microbiota. Innate microbial sensing by epithelial cells, DCs, and macrophages is mediated through PRRs such as TLRs and NLRs. Activation of PRRs on innate cells induces various pathways that mediate microbial killing and activate adaptive cells. DCs present antigens to naïve CD4⁺ T cells in secondary lymphoid organs (Peyer’s patches, mesenteric lymph nodes) where factors such as the phenotype of the antigen presenting cells and cytokine milieu modulate differentiation of CD4⁺ T-cell subsets (Th1, Th2, Th17, Treg) with characteristic cytokine and intestinal homing profiles. (B) Tolerance mechanisms: Defense mechanisms that limit microbial entry into intestinal tissues also serve as a mechanism of tolerance. Activation of PRRs on the unique populations of macrophages and DCs in the intestinal lamina propria does not result in secretion of proinflammatory cytokines, in contrast to similar activation of systemic innate cells. DC present antigen to T cells in the Peyer’s patches and mesenteric lymph nodes, which can lead to differentiation of Treg populations, regulated by IL-10, TGF-β, and retinoic acid. Thymic stromal lymphopoietin (TSLP) and other factors secreted by epithelial cells in the intestinal environment can contribute to tolerance of intestinal immune cells.