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Publication : A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage.

First Author  Ngo VL Year  2018
Journal  Proc Natl Acad Sci U S A Volume  115
Issue  22 Pages  E5076-E5085
PubMed ID  29760082 Mgi Jnum  J:263562
Mgi Id  MGI:6159978 Doi  10.1073/pnas.1718902115
Citation  Ngo VL, et al. (2018) A cytokine network involving IL-36gamma, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage. Proc Natl Acad Sci U S A 115(22):E5076-E5085
abstractText  The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36gamma is a potent inducer of IL-23 both in vitro and in vivo. IL-36gamma-induced IL-23 required Notch2-dependent (CD11b(+)CD103(+)) dendritic cells (DCs), but not Batf3-dependent (CD11b(-)CD103(+)) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-kappaB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36gamma-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36gamma could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36gamma, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.
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