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  • p97 br ILCs as chemosensory cells

    2020-08-05


    ILCs as chemosensory cells The Aryl Hydrocarbon Receptor (AHR) is a ligand-activated TF that binds indoles derived from the bacterial degradation of dietary tryptophan, as well as tryptophan metabolites contained in vegetables [79], bacterial toxins [] and environmental polycyclic hydrocarbons (Figure 3). AHR drives the development of ILC3 and their production of IL-22 [81], providing a mechanism to adapt the intestinal innate immune system to nutrition and intestinal flora. NK p97 also express AHR, which was required for optimal NK cell cytotoxicity, IFN-γ production and anti-tumor activity [82]. Studies using genetic mouse models and various diets have shown that sensing of vitamin A metabolites in utero is crucial for the prenatal differentiation of LTi cells, which control the size of secondary lymphoid tissues and the generation of protective immune responses in adults []. In adult mice, RA signaling favors the development of ILC3s over ILC2s. Consequently, vitamin-A-deficient mice fail to control C. rodentium infection but are resistant to helminth infection []. In contrast to the immunostimulatory functions of vitamin A metabolites, vitamin D is predominantly immunosuppressive for ILCs and downregulates IL-22 expression in ILC3 [85]. Consequently, vitamin D receptor knockout mice have more IL-22-producing ILC3, secrete more antibacterial peptides and are more resistant to C. rodentium infection [86]. In addition to vitamins and metabolites, ILCs sense a range of lipid mediators, such as prostaglandins (PG), leukotrienes, and oxysterols, which are released during inflammation and tissue repair, in addition to the blood borne lipid, sphingosine-1-phosphate (S1P). PGD2 and cysteinyl leukotrienes bind to the CRTH2 and CysLT1R receptors, respectively, to enhance ILC2 cytokine production [87, 88, 89], whereas PGE2 inhibited GATA-3 expression and IL-5 and IL-13 production by ILC2s in response to IL-25, IL-33 and TSLP through the PTGER-2 and PTGER-4 receptors. [90]. PGE2 also downregulated the expression of IL-2 receptor α (CD25) leading to reduced responsiveness to IL-2 and ILC2 proliferation. In contrast, oxysterols, such as 7α,25-hydroxycholesterol, activate the GPR183 receptor to promote ILC3 migration and localization to cryptopatches and isolated lymphoid follicles []. S1P activates S1PR-1, S1PR-4 and S1PR-5 to promote lymphatic entry, blood circulation and migration of iILC2s to distal sites [92].
    ILCs anticipate neuronal-derived factors Recent studies have revealed that ILCs express receptors for neural peptides, thus enabling cross-talk with the peripheral nervous system. ILC3s express RET (Figure 2), which is a receptor for members of the glial cell-derived neurotrophic factor family of ligands (GFL) (Figure 3). Toll-like receptor signaling upregulates GFLs in response to bacterial infections and GFL binding to RET enhances ILC3 secretion of IL-17 and IL-22 []. ILC2s were found in close contact with enteric neurons that can produce vasoactive intestinal peptide (VIP), which engages VIP receptor to enhance ILC2 secretion of type 2 cytokines in response to helminth infections [94]. Enteric neurons can also release the peptide neuromedin U (NMU), which activates ILC2 cytokine secretion via NMU receptor 1 to stimulate mucus production by goblet cells and control of helminth infection [95, 96, 97]. Conversely, ILC2s express adrenergic receptor β2 (ADRB2) that can inhibit cytokine secretion [].