Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans

Abstract

Interleukin 10 (IL10) is a key anti-inflammatory cytokine that can inhibit proinflammatory responses of both innate and adaptive immune cells. An association between IL10 and intestinal mucosal homeostasis became clear with the discovery that IL10 and IL10 receptor (IL10R)-deficient mice develop spontaneous intestinal inflammation. Similarly, patients with deleterious mutations in IL10, IL10RA, or IL10RB present with severe enterocolitis within the first months of life. Here, we review recent findings on how IL10- and IL10R-dependent signaling modulates innate and adaptive immune responses in the murine gastrointestinal tract, with implications of their role in the prevention of inflammatory bowel disease (IBD). In addition, we discuss the impact of IL10 and IL10R signaling defects in humans and their relationship to very early-onset IBD (VEO-IBD).

Keywords: Colitis; IBD; IL10; IL10 receptor; Microbiome; Very early-onset IBD.

Figure 5.1

The IL10/IL10R signaling pathway. IL10 signals through heterotetrameric IL10R complex comprising of IL10Rα (IL10R1 in humans) and IL10Rβ (IL10R2 in humans). Binding of IL10 to its receptor leads to JAK1- and TYK2-mediated phosphorylation of STAT3. Following phosphorylation, STAT3 forms a homodimer and undergoes nuclear translocation where it binds to STAT3-binding elements of IL10-responsive genes and drives expression of anti-inflammatory mediators that block various inflammatory pathways. IL10-responsive gene products inhibit TLR4 signaling at the level of IRAK and TRAF6 resulting in reduced NF-κB-mediated expression of IL6, TNF, and IL1 and also inhibit IL6 signaling at the level of gp30 receptor subunit. MyD88, myeloid differentiation primary response gene (88); TLR, toll-like receptor; IRAK, interleukin-1 receptor-associated kinase; TRAF, TNF receptor-associated factor.

Figure 5.2

Il10rb^−/− mice develop spontaneous colitis. Histology images (4×) of distal colonic tissue obtained from 6-month-old wild type and Il10rb^−/− mice.

Figure 5.3

Increase in IL17A⁺ and INFγ⁺ CD4⁺ T cells in the lamina propria of Il10rb^−/− mice. Lamina propria cells of 4-month-old WT and Il10rb^−/− mice were obtained, and stimulated with phorbol myristate acetate (PMA) and ionomycin for 4 h, in the presence of GolgiStop. Plots gated on CD4⁺ T cells.