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  • In pregnancy maternal uterine spiral artery SA remodeling

    2020-02-07

    In pregnancy, maternal uterine spiral artery (SA) remodeling is essential for ensuring efficient blood flow to the developing fetus. A subset of CD49a+Eomes+ decidual NK BAMB-4 (dNK) that actively secretes GFs, such as pleiotrophin and osteoglycin, have recently been described in humans and in mice. The GF-secreting function of this dNK subset was regulated by trophoblast-expressed HLA-G binding to LILRB1 (also know as ILT2) on dNK and deficiency in this subset impaired fetal development resulting in restricted fetal growth [76]. Thus, engaging with GF pathways by ILCs may operate during development, malignancy and possible also during infections with pathogens that have captured GFs or can induce their expression.
    Complement arouses ILC functions The complement system is an evolutionary ancient system of immune defense. Properdin (also known as complement factor P) is a plasma glycoprotein that binds to microbial surfaces and apoptotic cells and triggers the alternate pathway of complement that leads to the formation of the membrane attack complex and target cell lysis. Human and mouse ILC1 and a subset of ILC3 express the activating immunoreceptor NKp46 (Figure 2). Properdin binds to NKp46 and NKp46 and ILC1s were required for resistance to Neisseria meningitidis opsonized by properdin []. Since NKp46 mediates both positive and negative immunoregulation [78], it will be important to delineate the pathways regulated by the NKp46-properdin interaction in different disease models including cancer.
    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 cells 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].