Regulation of intestinal homeostasis by innate immune cells

Abstract

The intestinal immune system has an ability to distinguish between the microbiota and pathogenic bacteria, and then activate pro-inflammatory pathways against pathogens for host defense while remaining unresponsive to the microbiota and dietary antigens. In the intestine, abnormal activation of innate immunity causes development of several inflammatory disorders such as inflammatory bowel diseases (IBD). Thus, activity of innate immunity is finely regulated in the intestine. To date, multiple innate immune cells have been shown to maintain gut homeostasis by preventing inadequate adaptive immune responses in the murine intestine. Additionally, several innate immune subsets, which promote Th1 and Th17 responses and are implicated in the pathogenesis of IBD, have recently been identified in the human intestinal mucosa. The demonstration of both murine and human intestinal innate immune subsets contributing to regulation of adaptive immunity emphasizes the conserved innate immune functions across species and might promote development of the intestinal innate immunity-based clinical therapy.

Keywords: IBD; Innate immunity; Intestinal homeostasis.

Figure 1

Murine CD103⁺ dendritic cells. (A) IRF4⁺CD103⁺CD11b⁺ dendritic cells induce Th17 development through the production of IL-6. (B) IL-23-expressing TLR5⁺CD103⁺CD11b⁺ dendritic cells promote differentiation of Th1 and Th17 cells and induce antimicrobial peptide RegIIIg from epithelial cells through the induction of IL-22 by innate lymphoid cells (ILC). (C) CD103⁺CD11c⁺ dendritic cells induce differentiation of Foxp3⁺ T_reg cells through the production of retinoic acid and TGF-β. (D) B. breve enhances accumulation of Tr1 cells via TLR2 signaling-dependent activation of CD103⁺CD11c⁺ dendritic cells.

Figure 2

Murine innate myeloid subsets. (A) CX₃CR1^intermediateCD70⁺CD11b⁺ dendritic cells can induce Th17 cell development in a commensal bacteria-derived ATP dependent manner. (B) M_reg cells tightly regulate Th17/Th1 cell proliferation in an IL-10/Stat3-dependent fashion. (C) Macrophages mediate sustained expression of Foxp3 in T_reg cells by producing IL-10. In addition, macrophage-derived IL-10 acts on intestinal macrophages, dendritic cells and neutrophils to inhibit colitogenic cytokine production including IL-12p40, TNF-α, IL-23 and IL-6, which contribute to the initiation of Th1/Th17 cell development.

Figure 3

Human intestinal innate myeloid cells. (A) At steady state, CD14⁺ macrophages play important roles in maintaining immune tolerance by producing IL-10. In contrast, IRF4-expressing CD103⁺ CD141^-SIRPα^high dendritic cells and CD14⁺CD163^low cells activate pro-inflammatory pathway for host defense through the promotion of Th17 development. (B) In patients with Crohn's disease, IL-23-expressing CD14⁺ macrophages enhance colitogenic IL-17 and IFN-γ-producing T cell differentiation and the activity of CD14⁺CD163^low cells to drive Th17 differentiation is increased.