Abstract
The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.
Highlights
The innate immune system is usually considered as the first line of defense against invading microorganisms, its contribution is increasingly emerging in several noninfectious diseases, including atherosclerosis (Chávez-Sánchez et al, 2014) and its ischemic complications (Courties et al, 2014), inflammatory bowel disease (Levine and Segal, 2013), systemic sclerosis (O’Reilly, 2014), multiple sclerosis, and other demyelinating disease (Mayo et al, 2012), neurodegenerative disease (Boutajangout and Wisniewski, 2013), and only as example, obesity (Lumeng, 2013) and diabetes (Lee, 2014) or that innate immunity play a role in tumor recognition (Marcus et al, 2014) and as a barrier to organ transplantation
We have recently shown that human neutrophils express mRNA for all α- and β-AR, in the following order: β3 > β2 > α1A > α1B ∼ α2A ∼ β1 = α1D = α2C and that exposure of cells to IL-8, a potent proinflammatory CXC-chemokine that promotes neutrophil chemotaxis and degranulation, increases mRNA levels of all AR, and that adrenaline, probably through the involvement of β-AR, profoundly affects neutrophil function (Scanzano et al, 2015)
Adrenergic pathways represent the main channel of communication between the nervous system and the immune system, their role has received more attention as regards modulation of adaptive immunity (Elenkov et al, 2000; Cosentino and Marino, 2013; Marino and Cosentino, 2013), in comparison to innate immunity
Summary
Physiology and Pharmacology of Adrenergic Pathways Adrenaline (“near the kidney,” from Latin roots ad and renes; US: epinephrine, from the Greek roots epi and nephros, i.e., “on the kidney”) belongs together with noradrenaline (the prefix “nor” standing for nitrogen öhne radikal, indicating the absence of a methyl group) to Abbreviations: DC, Dendritic cells; NK, Natural killer cells; γδ T lymphocytes, Gamma Delta T lymphocytes; AR, Adrenoceptors; Th, T helper lymphocytes; LC, Locus coeruleus; cAMP, Cyclic adenosine monophosphate; CNS, Central nervous system; ILC, Innate lymphoid cells; PRR, Pattern recognition receptors; PAMP, Pathogen-associated molecular patterns; DAMP, Danger (or damage)-associated molecular patterns; TLR, Toll-like receptors; NLR, NOD-like receptors; CLR, C-type lectin receptors; RLR, RIG-I-like receptors; ALR, AIM2-like receptors; FPR, Formyl peptide receptors; gC1qR, gC1q receptor; SPLUNC1, Nasal epithelial clone 1; hBD, Human β-defensin; HNP, Human neutrophil peptide; MAO, Monoamine oxidase; VMAT, Vesicular monoamine transporter; EPO, Eosinophil peroxidase; TNF, Tumor necrosis factor; SCF, Stem cell factor; MIP, Macrophage inflammatory protein; LPS, Lipopolysaccharide; IL, Interleukine; IE, Immediateearly; MMP, Matrix metalloproteinases; PKC, Protein kinase C; MHC, Major histocompatibility complex; PLC, Phospholipase C; PKA, Protein kinase A; CpG-C ODN, Type-C CpG oligodeoxynucleotides; COX, Cyclooxygenase; THP-1, Human microglia-like cells; MDSC, Myeloid-derived suppressor cells. The sympathetic nervous system, through its preganglionic fibers, stimulates chromaffin cells in the adrenal glands to release into the bloodstream adrenaline (∼80% in humans) and noradrenaline (∼20%). Some central nervous system (CNS) neurons, mainly located in the medullary reticular formation, utilize adrenaline as the main neurotransmitter, possibly contributing to the modulation of eating behavior and to blood pressure regulation. Main direct effects of noradrenaline and adrenaline on peripheral tissues include: smooth muscle contraction in blood vessels supplying skin, kidney, and mucous membranes, stimulation of exocrine glands, smooth muscle relaxation in the gut wall, bronchi, and blood vessels supplying skeletal muscle, increases of heart rate and force of contraction, increased glycogenolysis in liver and muscle, lipolysis in adipose tissue, thermogenesis in the brown adipose tissue, modulation of the secretion of insulin and rennin (Feldman et al, 1997)
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