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      Role of adrenergic receptor signalling in neuroimmune communication

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          Abstract

          Neuroimmune communication plays a crucial role in maintaining homeostasis and promptly responding to any foreign insults. Sympathetic nerve fibres are innervated into all the lymphoid organs (bone marrow, thymus, spleen, and lymph nodes) and provide a communication link between the central nervous system (CNS) and ongoing immune response in the tissue microenvironment. Neurotransmitters such as catecholamines (epinephrine and norepinephrine) bind to adrenergic receptors present on most immune and non-immune cells, establish a local neuroimmune-communication system, and help regulate the ongoing immune response. The activation of these receptors varies with the type of receptor-activated, target cell, the activation status of the cells, and timing of activation. Activating adrenergic receptors, specifically β-adrenergic signalling in immune cells leads to activation of the cAMP-PKA pathway or other non-canonical pathways. It predominantly leads to immune suppression such as inhibition of IL-2 secretion and a decrease in macrophages phagocytosis. This review discusses the expression of different adrenergic receptors in various immune cells, signalling, and how it modulates immune cell function and contributes to health and diseases. Understanding the neuroimmune communication through adrenergic receptor signalling in immune cells could help to design better strategies to control inflammation and autoimmunity.

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          Highlights

          • Primary and secondary lymphoid organs are innervated with sympathetic nerve fibres.

          • Adrenergic receptor expression on immune and non-immune cells establishes a local neuroimmune communication system.

          • Adrenergic receptor signalling in immune cells controls the differentiation and function of various immune cells.

          • Modulating adrenergic receptor signalling with a specific agonist or antagonist also affect the immune response.

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          Most cited references234

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          The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.

          The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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            The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy

            Natural killer (NK) cells are innate immune cells that show strong cytolytic function against physiologically stressed cells such as tumor cells and virus-infected cells. NK cells show a broad array of tissue distribution and phenotypic variability. NK cells express several activating and inhibitory receptors that recognize the altered expression of proteins on target cells and control the cytolytic function. NK cells have been used in several clinical trials to control tumor growth. However, the results are encouraging only in hematological malignancies but not very promising in solid tumors. Increasing evidence suggests that tumor microenvironment regulate the phenotype and function of NK cells. In this review, we discussed the NK cell phenotypes and its effector function and impact of the tumor microenvironment on effector and cytolytic function of NK cells. We also summarized various NK cell-based immunotherapeutic strategies used in the past and the possibilities to improve the function of NK cell for the better clinical outcome.
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              Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.

              Phosphorylation of G protein-coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arrestins. These multifunctional adaptor proteins desensitize GPCRs, by reducing receptor coupling to G proteins and facilitating receptor internalization, and mediate GPCR signaling through β-arrestin-specific pathways. Detailed mapping of the phosphorylation sites on GPCRs targeted by individual GRKs and an understanding of how these sites regulate the specific functional consequences of β-arrestin engagement may aid in the discovery of therapeutic agents targeting individual β-arrestin functions. The β(2)-adrenergic receptor (β(2)AR) has many serine and threonine residues in the carboxyl-terminal tail and the intracellular loops, which are potential sites of phosphorylation. We monitored the phosphorylation of the β(2)AR at specific sites upon stimulation with an agonist that promotes signaling by both G protein-mediated and β-arrestin-mediated pathways or with a biased ligand that promotes signaling only through β-arrestin-mediated events in the presence of the full complement of GRKs or when either GRK2 or GRK6 was depleted. We correlated the specific and distinct patterns of receptor phosphorylation by individual GRKs with the functions of β-arrestins and propose that the distinct phosphorylation patterns established by different GRKs establish a "barcode" that imparts distinct conformations to the recruited β-arrestin, thus regulating its functional activities.
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                Author and article information

                Contributors
                Journal
                Curr Res Immunol
                Curr Res Immunol
                Current Research in Immunology
                Elsevier
                2590-2555
                25 November 2021
                2021
                25 November 2021
                : 2
                : 202-217
                Affiliations
                [1]National Centre for Cell Science (NCCS), Ganeshkhind, Pune, MH-411007, India
                Author notes
                []Corresponding author. National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune, MH-411007, India. glal@ 123456nccs.res.in
                Article
                S2590-2555(21)00023-8
                10.1016/j.crimmu.2021.11.001
                9040148
                35492402
                e0953d90-12f6-4823-bb79-4d9efebf16d5
                © 2021 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 September 2021
                : 11 November 2021
                : 17 November 2021
                Categories
                Review Article

                sns, sympathetic nervous system,l-dopa, l-dihydroxyphenylalanine,ac, adenylate cyclase,grk, g protein-coupled receptor kinase,cns, central nervous system,dcs, dendritic cells,lps, lipopolysaccharide,tnf, tumor necrosis factor,pka, protein kinase a,pde, phosphodiesterase,camp, cyclic adenosine monophosphate,adrenaline,adrenergic receptors,epinephrine,nerve-driven immunity,neuroimmune communication,neurotransmitters,norepinephrine

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