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  • NECA synthesis br ILCs anticipate neuronal derived

    2021-04-16


    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 []. It has been shown that the vagus nerve can sense peripheral infections and/or tissue injuries via an afferent arc, which activates efferent neural circuits that modulate the progression of inflammatory responses [99]. Escherichia coli infection in mice triggers the production of NECA synthesis (ACh) by the vagal system, which can arouse the cholinergic receptors (CHRM)-1, -2, -4 and -5) and induce ILC3 production of resolution phase lipid mediators, such as the protective immunoresolvent PCTR1 to promote myeloid cell responses, resolution of inflammation, and tissue repair []. Future studies are likely to reveal the expression and function of additional receptors for neuronal-derived mediators, expanding the impact of the peripheral nervous system to different aspects of ILC biology.
    Impact of the endocrine system on ILCs The neuroendocrine system is a key player in controlling hyperinflammation and prevention of tissue damage. Inflammatory cytokines stimulate the hypothalamic-pituitary-adrenal (HPA) axis to produce glucocorticoid (GC), which is a critical step in establishing tolerance to septic shock, although the cellular targets remain unclear (Figure 3). NK cells and ILC1 express GC receptor, which was required to limit IFN-γ production, permitting IL-10-dependent tolerance to microbial endotoxins [101] (Figure 2). Moreover, endogenous GC induced the expression of the checkpoint receptor PD-1 on NK cells, which limited IFN-γ production by splenic NK cells and preventing virus-induced immunopathology without compromising viral clearance []. Hormones are active at many stages of development. Fetal trophoblast cells express the pregnancy-related peptide hormone adrenomedullin that binds to the Calcitonin receptor-like receptor (CALCRL) to promote the recruitment and activation of maternal uNK cells to the placenta and facilitation of maternal SA remodeling [103]. Sex hormones can regulate many autoimmune and inflammatory diseases, such as asthma. For example, asthma is twice as prevalent in women compared to men. Moreover, administration of testosterone and the downstream active hormone, 5α-dihydrotestosterone, reduced the numbers and IL-5 and IL-13 expression from ILC2 and attenuated allergen-induced airway hypersensitivity in mice. Interestingly, women with asthma have increased ILC2s compared to men [], suggesting that sexual dimorphism in ILC2 numbers may explain higher susceptibility to asthma in women [].
    Concluding remarks
    Conflicts of interest statement
    References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
    Introduction Osteoporosis is a serious health problem affecting over 200 million people worldwide (Sedlak, Doheny, & Jones, 1998). Osteoporosis is characterized by a decrease in bone mineral density (BMD) and a weakening of bone microarchitecture, leading to loss of bone mineralized mass, bone fragility, and increased susceptibility to fracture (Kanis and Gluer, 2000, Xie et al., 2016). Osteoporosis is frequently described as a silent disease because there are often no symptoms until fracture occurs (Lydick, Martin, & Yawn, 1996). Osteoporosis is especially prevalent among postmenopausal women with western lifestyles (Alekel et al., 1999). During menopause, estrogen deficiency affects bone metabolism (Riggs, Khosla, & Melton, 1998); therefore, to prevent osteoporosis it is essential to control the bone health of menopausal women by regulating estrogen. Osteoporosis in menopausal women is mainly managed using estrogen replacement therapy, bisphosphonates, selective estrogen receptor modulators, and calcitonin (Prince et al., 1991). Unfortunately, the positive effects of these drugs are counteracted by serious side effects such as increased risk of cancer and thromboembolism (Hoibraaten et al., 2000, Schairer et al., 2000). Therefore, it is necessary to search for new, less toxic, drugs that can prevent osteoporosis. The potential medical applications of phytochemicals are becoming more recognized in the scientific community (Monteiro, Queiros, Lopes, Pedro, & Macedo, 2018), and there have been many efforts to identify the effects of natural compounds on bone health in women with menopausal symptoms (Dodin et al., 2005, Levis et al., 2011, Wuttke et al., 2003).