Modulation of Immune Cell Function by α1-Adrenergic Receptor Activation

doi:10.1016/B978-0-12-384921-2.00006-9

Current Topics in Membranes

Volume 67, 2011, Pages 113-138

https://doi.org/10.1016/B978-0-12-384921-2.00006-9 Get rights and content

Publisher Summary

This chapter discusses the modulation of immune cell function by α₁-adrenergic receptor activation. The sympathetic nervous system regulates human immune system functions through the epinephrine (Epi) and norepinephrine (NE) activation of adrenergic receptors (ARs) expressed on immune competent cell populations. The anti-inflammatory effects that are most often attributed to increased sympathetic activity have been shown to occur through β₂- and α₂-AR stimulation. However, dichotomous AR effects on immune system responses are becoming increasingly apparent. The endogenous catecholamines, Epi and NE, are critical for initiating the fight or flight response of the sympathetic nervous system. Epi and NE are released from peripheral neurons and the adrenal medulla in response to physical as well as psychological stress to regulate a number of physiological functions, including energy metabolism, cardiovascular homeostasis, and thermal adaptation. The human innate immune system is a nonspecific means of defense against pathogenic challenges. This generic means of defense is thought to be a more evolutionary primitive design compared to the adaptive immune system.

Section snippets

Overview

The sympathetic nervous system regulates human immune system functions through epinephrine (Epi) and norepinephrine (NE) activation of adrenergic receptors (ARs) expressed on immunocompetent cell populations. The anti-inflammatory effects that are most often attributed to increased sympathetic activity have been shown to occur through β₂- and α₂-AR stimulation. However, dichotomous AR effects on immune system responses are becoming increasingly apparent. Reports of α₁-AR expression on immune

α₁-Adrenergic Receptor Expression in the Immune System

The three characterized α₁-AR subtypes (α_1A-, α_1B-, and α_1D-) are differentially expressed in many organs and cells of the immune system. Investigation of α₁-AR expression in immune tissues has relied heavily on RT-PCR analysis. Little information is available about α₁-AR subtype localization at the protein level in the immune system since commercially available antibodies have been shown to be nonselective in wild-type and transgenic animal models (Jensen et al., 2009). Therefore, most studies

The Role of α₁-Adrenergic Receptors in the Innate Immune System

The human innate immune system is a nonspecific means of defense against pathogenic challenges. This generic means of defense is thought to be a more evolutionary primitive design compared to the adaptive immune system. Protective mechanisms initiated by innate immune responses include recruitment of immunocompetent cells at sites of infection, production of chemical mediators such as cytokines, activation of the complement cascade to identify and clear invading pathogens, the removal of

α₁-Adrenergic Receptor Influences on the Adaptive Immune System

The highly specialized adaptive immune system allows the host to recognize and remember specific pathogens so that a strong attack can be mounted every time the pathogen is reencountered. The system is highly pliant allowing a small number of host genes to generate huge numbers of diverse antigen receptors uniquely expressed on individual lymphocytes. The adaptive immune system functions to recognize specific nonself antigens to generate maximal effective responses tailored to eliminate

Spleen

The spleen is an important immune system organ responsible for removing old red blood cells, maintaining a blood reserve, recycling elemental iron, synthesizing antibodies as well as retaining half the body's monocytes, which allows them to move into injured tissues for differentiation into DCs and macrophages. The spleen is richly innervated by the sympathetic nerves, which affects its physiology (Felten et al., 1987). Reports of high transcriptional expression for all three α₁-AR subtypes in

α₁-Adrenergic Receptors in Disease States

Given the summary of information to date, an immunomodulatory role under pathophysiological conditions can be brought forward for α₁-ARs expressed in the immune system. For example, α₁-AR activation has been proposed to be important in the development of experimental autoimmune encephalomyelitis (EAE), an inflammatory demyelinating disease of the central nervous system that is often used as a model for multiple sclerosis (Brosnan et al., 1985). Development of EAE results from T lymphocyte

Conclusions

α₁-AR expression on various immunocompetent cell populations has been reported and shown to be regulated during pathophysiological processes. However, α₁-AR function to modulate immune cell responses is just beginning to be understood. α₁-AR activation appears to alter production of inflammatory mediators from certain cell types including monocytes, macrophages, and myocytes. Additionally, α₁-AR signaling plays a role in DC migration, lymphopoiesis, and mast cell degranulation. A better

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Cited by (54)

Inflammation induces α<inf>1</inf>-adrenoceptor expression in peripheral blood mononuclear cells of patients with complex regional pain syndrome
2024, Brain, Behavior, and Immunity
Persistent regional and systemic inflammation may promote pain and hyperalgesia in complex regional pain syndrome (CRPS). In this study, we investigated whether stimulation of α₁-adrenoceptors (α₁-AR) on peripheral blood mononuclear cells (PBMC) might contribute to this inflammatory state. PBMC were isolated from venous blood collected from 21 CRPS patients and 21 sex and age-matched controls. Lipopolysaccharide (LPS), a bacterial toxin, was administered to cultured PBMC for 24 h to trigger inflammation. Exposure to LPS resulted in heightened gene expression of α₁-AR subtype B (α_1B-AR) in PBMC of CRPS patients relative to controls. Interleukin (IL)-1β and IL-6 levels did not change when the α₁-AR agonist phenylephrine was administered to naïve PBMC. However, α₁-AR stimulation following LPS treatment increased IL-6 mRNA and protein levels in PBMC of patients and controls. To investigate the possible consequence of heightened IL-6 levels on immunoglobulin G antibody production, PBMC were stimulated with CD40 ligand and IL-21 to generate plasmablasts (B cells that secrete antibodies). This response was similar in patients and controls. Adding IL-6 to the cell culture medium increased plasmablast differentiation in controls and antibody production both in patients and controls. These findings suggest that the inflammatory cascade associated with elevated levels of IL-6 may generate α_1B-AR expression in CRPS PBMC. A reciprocal interaction between heightened α₁-AR expression in PBMC and IL-6 secretion may contribute to systemic inflammation and antibody production in CRPS.
Neuroimmune interplay in kidney health and disease: Role of renal nerves
2023, Autonomic Neuroscience: Basic and Clinical
Renal nerves and their role in physiology and disease have been a topic of increasing interest in the past few decades. Renal inflammation contributes to many cardiorenal disease conditions, including hypertension, chronic kidney disease, and polycystic kidney disease. Much is known about the role of renal sympathetic nerves in physiology – they contribute to the regulation of sodium reabsorption, renin release, and renal vascular resistance. In contrast, far less is known about afferent, or “sensory,” renal nerves, which convey signals from the kidney to the brain. While much remains unknown about these nerves in the context of normal physiology, even less is known about their contribution to disease states. Furthermore, it has become apparent that the crosstalk between renal nerves and the immune system may augment or modulate disease. Research from other fields, especially pain research, has provided critical insight into neuroimmune crosstalk. Sympathetic renal nerve activity may increase immune cell recruitment, but far less work has been done investigating the interplay between afferent renal nerves and the immune system. Evidence from other fields suggests that inflammation may augment afferent renal nerve activity. Furthermore, these nerves may exacerbate renal inflammation through the release of afferent-specific neurotransmitters.
Re-directing anomedicines to the spleen: A potential technology for peripheral immunomodulation
2022, Journal of Controlled Release
Modulation of peripheral immune cells in the spleen plays a key role in many life-threatening conditions such as stroke. Immune cell changes can lead to the excessive release of pro-inflammatory cytokines into the circulation and preferential loss of innate immune cells which can further exacerbate tissue damage and predispose patients to infectious complications. Reversing these processes represents an attractive treatment strategy and has shown to have beneficial effects in animal models of ischemic stroke, sepsis, traumatic brain injury (TBI) as well as myocardial infraction (MI). However, systemic interventions are often challenging to deliver due to the non-selective broad range of action of many treatments. More selective targeted treatment approaches are therefore desirable. The spleen is considered a natural filtration site for many nanomaterials due to the spontaneous tendency of this organ to filter blood-borne molecules. This selective targeting of nanomaterials to the spleen therefore offers considerable potential in the management of many conditions affected by peripheral inflammation. In this review, we will explore the key nanomaterials-related parameters that mediate splenic targeting and how these could influence the actual localization and function of nanomaterials once in the spleen. We aim to emphasize the potential of utilising nanomaterials as selective tools for peripheral immunomodulation to accelerate clinical translation.
Adrenergic receptor gene expression in bovine leukocytes
2022, Developmental and Comparative Immunology
The α- and β-adrenergic receptors (ARs) bind the stress hormones epinephrine (E), norepinephrine (NE), and dopamine and activate diverse physiological responses. A lack of information on AR gene expression in leukocytes limits our understanding of how stress alters immune function. Quantitative analyses of AR gene expression was completed for bovine leukocytes. Individual leukocyte lineages and subpopulations within lineages were isolated with high-speed cell sorting to facilitate a targeted analysis of AR gene expression. These analyses confirmed all 9 AR genes were expressed in bovine leukocytes with marked differences in AR gene expression when comparing among leukocyte lineages. Furthermore, separation of polymorphonuclear cells into neutrophils and eosinophils revealed these key innate immune cells also differ significantly in AR gene expression. This study provides the first comprehensive survey of AR gene expression in immune cells of any mammalian species and provides insight into conflicting reports that stress can either activate or suppress immune function.
In silico drug repurposing in COVID-19: A network-based analysis
2021, Biomedicine and Pharmacotherapy
Citation Excerpt :
Recent evidence highlighted that these drugs may have an effect on both innate and adaptive immunity: Phenotyazine and antipsychotic drugs have known effects on α-adrenergic and histaminergic receptors, and could therefore act as possible immune system modulators [49,63]. Moreover, different drugs belonging to this class were shown to possess antiviral properties, suggesting potential repurposing for COVID-19 [64].
The SARS-CoV-2 pandemic is a worldwide public health emergency. Despite the beginning of a vaccination campaign, the search for new drugs to appropriately treat COVID-19 patients remains a priority. Drug repurposing represents a faster and cheaper method than de novo drug discovery. In this study, we examined three different network-based approaches to identify potentially repurposable drugs to treat COVID-19. We analyzed transcriptomic data from whole blood cells of patients with COVID-19 and 21 other related conditions, as compared with those of healthy subjects. In addition to conventionally used drugs (e.g., anticoagulants, antihistaminics, anti-TNFα antibodies, corticosteroids), unconventional candidate compounds, such as SCN5A inhibitors and drugs active in the central nervous system, were identified. Clinical judgment and validation through clinical trials are always mandatory before use of the identified drugs in a clinical setting.
Splenic Denervation Attenuates Repeated Social Defeat Stress-Induced T Lymphocyte Inflammation
2021, Biological Psychiatry Global Open Science
Posttraumatic stress disorder (PTSD) is a devastating psychological disorder. Patients with PTSD canonically demonstrate an increased risk for inflammatory diseases as well as increased sympathetic tone and norepinephrine outflow. Yet, the exact etiology and causal nature of these physiologic changes remain unclear. Previously, we demonstrated that exogenous norepinephrine alters mitochondrial superoxide in T lymphocytes to produce a proinflammatory T helper 17 phenotype and observed similar T helper 17 polarization in a preclinical model of PTSD. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma–induced T lymphocyte inflammation.
Repeated social defeat stress (RSDS) is a preclinical murine model that recapitulates the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation was performed to deduce the contribution of splenic sympathetic nerves to RSDS-induced inflammation. Denervation or sham operation was performed in 85 C57BL/6J mice, followed by RSDS or control paradigms. Animals were assessed for behavioral, autonomic, inflammatory, and redox profiles.
Denervation did not alter the antisocial or anxiety-like behavior induced by RSDS. In circulation, denervation/RSDS animals exhibited diminished levels of T lymphocyte–specific cytokines (interleukin 2 [IL-2], IL-17A, and IL-22) compared with intact animals, whereas other nonspecific inflammatory cytokines (e.g., IL-6, tumor necrosis factor α, and IL-10) were unaffected by denervation. Importantly, denervation specifically ameliorated the increases in RSDS-induced T lymphocyte mitochondrial superoxide, T helper 17 polarization, and proinflammatory gene expression with minimal impact to non–T lymphocyte immune populations.
Overall, our data suggest that sympathetic nerves regulate RSDS-induced splenic T lymphocyte inflammation but play less of a role in the behavioral and non–T lymphocyte inflammatory phenotypes induced by this psychological trauma paradigm.

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Chapter 6 - Modulation of Immune Cell Function by α1-Adrenergic Receptor Activation

Publisher Summary

Section snippets

Overview

α1-Adrenergic Receptor Expression in the Immune System

The Role of α1-Adrenergic Receptors in the Innate Immune System

α1-Adrenergic Receptor Influences on the Adaptive Immune System

Spleen

α1-Adrenergic Receptors in Disease States

Conclusions

J Allergy Clin Immunol

Brain Res Bull

J Allergy Clin Immunol

Biochem Biophys Res Commun

Mol Immunol

J Neuroimmunol

J Neuroimmunol

Brain Behav Immun

Curr Biol

J Neuroimmunol

Brain Behav Immun

Blood

Blood

Neuropharmacology

J Neuroimmunol

Pharmacol Res

J Neuroimmunol

Biochim Biophys Acta

J Neuroimmunol

J Neuroimmunol

J Pharmacol Sci

Prog Neuropsychopharmacol Biol Psychiatry

Reentry of T cells to the adult thymus is restricted to activated T cells

J Exp Med

Molecular cloning of α1d-adrenergic receptor and tissue distribution of three α1-adrenergic receptor subtypes in mouse

J Neurochem

LPS-induced blood neutrophilia is inhibited by α1-adrenoceptor antagonists: A role for catecholamines

J Leukoc Biol

Cutting edge: The mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (α integrin, very late antigen-2)

J Immunol

Expression of α-AR subtypes in T lymphocytes and role of the α-ARs in mediating modulation of T cell function

Neuroimmunomodulation

Prazosin, an α1-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat

Proc Natl Acad Sci USA

Cytokines down-regulate α1-adrenergic receptor expression during endotoxemia

Crit Care Med

Comparison of guinea-pig, bovine and rat α1-adrenoceptor subtypes

Br J Pharmacol

Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases

Ann N Y Acad Sci

Alpha adrenergic and mu-2 opioid receptors are involved in morphine-induced suppression of splenocyte natural killer activity

J Pharmacol Exp Ther

Lateralization and catecholaminergic neuroimmunomodulation: Prazosin, an α1/α2-adrenergic receptor antagonist, suppresses interleukin-1 and increases interleukin-10 production induced by lipopolysaccharides

Neuroimmunomodulation

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

Pharmacol Rev

Noradrenergic sympathetic neural interactions with the immune system: Structure and function

Immunol Rev

Phagocyte-derived catecholamines enhance acute inflammatory injury

Nature

Chapter 6 - Modulation of Immune Cell Function by α₁-Adrenergic Receptor Activation

α₁-Adrenergic Receptor Expression in the Immune System

The Role of α₁-Adrenergic Receptors in the Innate Immune System

α₁-Adrenergic Receptor Influences on the Adaptive Immune System

α₁-Adrenergic Receptors in Disease States

Molecular cloning of α_1d-adrenergic receptor and tissue distribution of three α₁-adrenergic receptor subtypes in mouse

LPS-induced blood neutrophilia is inhibited by α₁-adrenoceptor antagonists: A role for catecholamines

Prazosin, an α₁-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat

Cytokines down-regulate α₁-adrenergic receptor expression during endotoxemia

Comparison of guinea-pig, bovine and rat α₁-adrenoceptor subtypes

Lateralization and catecholaminergic neuroimmunomodulation: Prazosin, an α₁/α₂-adrenergic receptor antagonist, suppresses interleukin-1 and increases interleukin-10 production induced by lipopolysaccharides