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date: 15 December 2019

Autonomic Control of Immune Function

Summary and Keywords

Proper immune function is critical to maintain homeostasis, recognize and eliminate pathogens, and promote tissue repair. Primary and secondary immune organs receive input from the autonomic nervous system and immune cells express receptors for epinephrine, norepinephrine, and/or acetylcholine. Through direct signaling the autonomic nervous system controls immune function by altering immune cell development, initiating redistribution of immune cells throughout the body, and promoting molecular pathways that shift immune cell reactivity. This neuroimmune communication allows the autonomic nervous system to shape immune function based on physiological and psychological demands.

Keywords: autonomic, sympathetic, parasympathetic, immunity, innate, adaptive, neuroimmune, immunomodulation, epinephrine, norepinephrine, acetylcholine, monocyte, granulocyte, lymphocyte, inflammation, antibodies

Introduction

Several decades of research have uncovered bidirectional neuroimmune pathways that regulate immune function, physiology, and behavior (Dantzer, O’Connor, Freund, Johnson, & Kelley, 2008; Haroon, Raison, & Miller, 2012; Irwin & Cole, 2011). One of the primary efferent pathways (brain → periphery) is the autonomic nervous system. The autonomic nervous system is composed of two major branches, called the sympathetic and parasympathetic nervous systems (Wehrwein, Orer, & Barman, 2016). These branches are differentiated based on their anatomy, function, and generally divergent physiological effects. The sympathetic nervous system is composed of preganglionic neurons that originate in the central nervous system and directly synapse onto postganglionic neurons in vertebral ganglion. These postganglionic neurons innervate nearly all tissues and organs in the body. Upon sympathetic nervous system activation, postganglionic neurons release norepinephrine in target tissues and preganglionic neurons innervating the adrenal gland promote endocrine release of norepinephrine and epinephrine (Wehrwein et al., 2016). Physiological effects of sympathetic activation involve constriction of blood vessels, increased heart rate, and mobilization of energy resources, which are associated with the “fight or flight” response (Selye, 1936; Sternberg, 2006). The parasympathetic nervous system consists of preganglionic neurons that emanate from cervical and sacral segments of the spinal cord, and connect to postganglionic neurons near target tissues. These postganglionic neurons release acetylcholine in target tissues. The parasympathetic nervous system regulates several physiological functions to support homeostasis, including modulation of heart rate, salivation, production of tears, and digestion (Wehrwein et al., 2016).

In addition to these well-established physiological effects, activation of the sympathetic and parasympathetic divisions of the autonomic nervous system influence the immune system (Elenkov, Wilder, Chrousos, & Vizi, 2000). Early neuroanatomical studies showed that sympathetic neurons expressing the enzyme tyrosine hydroxylase directly innervate the bone marrow, spleen, and lymph nodes (Felten, Felten, Carlson, Olschowca, & Livnat, 1985). Despite no direct evidence that parasympathetic neurons innervate immune organs, converging studies indicate that release of acetylcholine from parasympathetic neurons can modulate inflammation through direct and indirect mechanisms (Tracey, 2009). Neuroimmune pathways can regulate immune function because immune cells and their progenitors express various combinations of receptors for epinephrine, norepinephrine, and acetylcholine. In particular, myeloid lineage immune cells, such as monocytes and granulocytes, express α‎-/β‎-adrenergic receptors, and each subtype of the muscarininc acetylcholine receptor (reviewed by Marino & Cosentino, 2013). Similarly, lymphoid lineage immune cells, such as T- and B-cells, express α‎-/β‎-adrenergic receptors (albeit lower levels than myeloid cells), each subtype of the muscarininc acetylcholine receptor, as well as specific subtypes of nicotinic acetylcholine receptors (Kawashima, Fujii, Moriwaki, & Misawa, 2012; Marino & Cosentino, 2013). Stimulation of these neurotransmitter receptors cause diverse functional responses that influence the development, distribution, and reactivity of immune cells (Dhabhar, Malarkey, Neri, & McEwen, 2012; Irwin & Cole, 2011; Nance & Sanders, 2007).

Many studies that examine autonomic control of immune function use model systems that augment sympathetic or parasympathetic activation. Rodent model systems that promote sympathetic activation include exposure to psychosocial or environmental stressors (i.e., social defeat or restraint). Following exposure to psychosocial or environmental stress increased levels of norepinephrine can be detected in circulation and immune organs, such as the bone marrow and spleen (Dhabhar et al., 2012; Hanke, Powell, Stiner, Bailey, & Sheridan, 2012). Another model system that leads to parasympathetic activation is exposure to pathogen-associated molecules (i.e., endotoxin or lipopolysaccharide), leading to immune responses that drive inflammation. These inflammatory signals are transmitted in the brain, which results in release of acetylcholine in several tissues, including the spleen (Tracey, 2009). These model systems are robust tools that enable study of dynamic neuroimmune interactions.

The Immune System and Its Functions

The immune system is a specialized network of cells that have a critical role in identifying pathogens or tissue damage, and then enacting molecular responses to eliminate pathogens, restore homeostasis, and promote tissue repair. All immune cells in the blood are generated through hematopoiesis, which is the differentiation of self-renewing stem cells that take up residence in the bone marrow. Specific molecular signals direct hematopoietic stem cells into distinct lineages. The immune system has two branches, the innate immune system and adaptive immune system. In broad terms, the innate immune system is characterized by nonspecific, yet rapid responses to pathogens, while the adaptive immune system maintains specific, long-term reactivity to pathogens that were previously encountered. The common myeloid progenitor generates the cellular components of the innate immune system, granulocytes, and monocytes. The common lymphoid progenitor generates T-cells and B-cells (and natural killer cells), which are the cellular constituents of the adaptive immune system. The primary factors that promote the common myeloid progenitor are monocyte-macrophage colony stimulating factor (M-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) (Hamilton & Achuthan, 2013). While differentiation of lymphocytes occurs outside of the bone marrow, it is well-established that the cytokine interleukin (IL)-7 is essential to promote the development of common lymphocyte progenitors (Gomes et al., 2016; Lai & Kondo, 2008). Following lineage specification these immune cells are released from the bone marrow into circulation, and traffic throughout the body and may be directed to other immune tissues, such as the spleen or thymus. In the spleen and thymus immune cells are further differentiated into effector cells (Bonilla & Oettgen, 2010).

Innate Immune Cells and Their Function

One common type of myeloid cell are granulocytes, which can be further divided into functionally different cells called neutrophils, eosinophils, and basophils. Granulocytes are appropriately named because they contain small granules that hold proteolytic and immunogenic molecules (Geering, Stoeckle, Conus, & Simon, 2013). In circulation, neutrophils are the most abundant granulocyte (and white blood cell) and they are rapidly recruited to sites of tissue injury or pathogen recognition (Kolaczkowska & Kubes, 2013). In this context, neutrophils patrol the body and upon encountering specific chemokine signals they will enter infected or damaged tissue. Further pathogen or damage-associated signals will cause degranulation or release of granules that contain various enzymes that break down cellular membranes as well as proteins or nucleic acids. Beyond release of these cytotoxic granules, neutrophils can phagocytose pathogens or cellular debris. After engulfment, these microbial or cellular components are eliminated through lysis and oxidative stress pathways (Dale, Boxer, & Liles, 2008). Eosinophils, basophils, and mast cells are less common granulocytes in the blood and display unique morphological and functional characteristics distinct from neutrophils. These differences are covered in detail in the review Geering et al., 2013.

Another important type of myeloid cell are monocytes, which are present in the blood and spleen. Overall monocytes constitute a small proportion of circulating leukocytes; however, their dynamic responses to varied stimuli enable them to direct innate immune responses. In broad terms, there are two distinct subsets of monocytes in circulation. Rodent studies indicate that monocytes can be separated based on specific cell surface marker expression: Ly6C-/lo/CX3CR1hi/CCR2lo and Ly6C+/hi/CX3CR1lo/CCR2hi (Geissmann, Jung, & Littman, 2003). These subsets are proposed to be similar to human monocyte subsets with markers CD14+/CD16/CX3CR1hi/CCR2lo and CD14+/CD16+/CX3CR1lo/CCR2hi, but these subsets can be further distinguished based on inflammatory and immunogenic potential (Geissmann et al., 2010). This is important because monocyte subsets appear to have different functional roles. Monocytes that express low levels of Ly6C (CX3CR1hi) contribute to homeostatic processes, such as patrolling blood vessels and integrating into tissues as macrophages (Auffray et al., 2007). Monocytes with high levels of Ly6C (CX3CR1lo) initiate and propagate inflammatory responses as they readily traffic to sites of pathogen recognition or tissue injury. Further studies indicate that monocytes can transition from Ly6C+/hi/CX3CR1lo/CCR2hi to Ly6C-/lo/CX3CR1hi/CCR2lo, suggesting that monocyte phenotypes are dynamic and exist on a continuum. Further when monocytes enter various tissues they can further differentiate into macrophages, which present other features like phagocytosis and antigen presentation (Murray & Wynn, 2011). Studies to determine mechanisms that promote the diversity of monocytes/macrophages are ongoing, but emerging evidence indicates that specific environmental and contextual cues engage a wide array of receptors to drive functional properties (Amit, Winter, & Jung, 2016; Ley, Pramod, Croft, Ravichandran, & Ting, 2016; Mosser & Edwards, 2008).

Tissue-resident macrophages are specialized myeloid cells that develop unique functions in specific tissues, including the Langerhans cells in the skin, alveolar macrophages in the lungs, and microglia in the brain. Seminal studies have explored the distinct functions of these macrophages, showing that tissue-specific environmental cues are critical mediators of their molecular profiles and immune reactivity (De Biase et al., 2017; Butovsky et al., 2014; Gosselin et al., 2014). Moreover, tissue-resident macrophages take up residence in various tissues early during development and undergo self-renewal or gradual replenishment by circulating monocytes (Davies, Jenkins, Allen, & Taylor, 2013). These long-lived macrophages have a significant influence on localized immune functions, and specific subsets of tissue-resident macrophages reside at interfaces with the external environment (e.g., skin, lungs); thereby, they often initiate innate immune responses to pathogens or tissue injury.

The key feature of the innate immune system is its capacity to mount rapid responses to pathogens as well as tissue injury. These rapid responses are mediated by specialized receptors called pattern recognition receptors (PRR), which identify conserved pathogen-associated molecular patterns (PAMPs). One type of PRR on rodent and human innate immune cells are toll-like receptors (TLRs). There are several subtypes of TLRs that respond to extracellular PAMPs, such as TLR-4, which recognizes cell wall components of gram-negative bacteria called lipopolysaccharide (LPS) (Akira & Takeda, 2004). Other reports note that TLR-4 can be stimulated by other endogenous ligands, including heat-shock proteins and fibronectin (Yu, Wang, & Chen, 2010). There are also TLR subtypes (e.g., TLR-3, TLR-7, TLR-9) that are localized in intracellular compartments and recognize intracellular PAMPs, including viral components in infected cells (Blasius & Beutler, 2010). These classical innate immune receptors converge on intracellular signaling pathways that enact molecular and cellular responses to fight infection. One specific signaling pathway linked to inflammation is the nuclear factor (NF)-κ‎B transcription factor. In particular, NF-κ‎B activation in neutrophils and monocytes leads to release of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α‎, interleukin(IL)-1β‎, and IL-6, following TLR stimulation (Medzhitov & Horng, 2009). These cytokines drive classical features inflammation, such as recruitment of other immune cells, fever, and increased pain sensitivity (Dantzer et al., 2008; Medzhitov, 2008). Similar inflammatory responses can be triggered by danger-associated molecular patterns (DAMPs) following tissue damage or injury. DAMPs are proteins or small molecules that are typically confined in intracellular compartments and can be released during cellular stress or damage (Fleshner & Crane, 2017; Maslanik et al., 2013). For instance, the protein called high mobility group box 1 (HMGB1) is generally sequestered in the nucleus; however, during cellular stress or damage HMGB1 is released. DAMPs are known to promote inflammatory responses via TLRs; however, receptors such as RAGE (receptor for advanced glycation end products) can propagate similar immune responses (Andersson & Tracey, 2011). Altogether PAMP and DAMP signaling through PRRs initiate the nonspecific, rapid inflammatory responses that are characteristic of the innate immune system. Despite the deleterious effects of innate immune activation it is important to note that inflammation is an essential defense mechanism that promotes resolution of infections or tissue injury, with the goal of restoring homeostasis (Chovatiya & Medzhitov, 2014; Medzhitov, 2008).

Following pathogen elimination or resolution of tissue injury innate immune cells, particularly macrophages, have a critical role in restoring homeostasis. In this context, macrophages produce anti-inflammatory cytokines, including IL-4, IL-10, and transforming growth factor (TGF)-β‎, that bind to their respective receptors and via direct and indirect mechanisms reduce pro-inflammatory cytokine production (Cavaillon, 2001). Beyond the release of anti-inflammatory cytokines macrophages produce tissue remodeling and growth factors, including arginase-1 and vascular-endothelial growth factor, which facilitate tissue repair (Novak & Koh, 2013). In addition, macrophages can be directed to clear cellular debris, such as apoptotic neutrophils and infected or damaged tissue. While the resolution of inflammation receives limited attention, recent studies indicate that these active and coordinated processes are essential to maintain tissue integrity and promote homeostasis (Buckley, Gilroy, Serhan, Stockinger, & Tak, 2012).

Adaptive Immune Cells and Their Functions

T-cells are a subset of lymphocytes that traffic from the bone marrow to the thymus and develop into effector cells with unique T-cell receptors that enable diverse functions, including antigen recognition and cytotoxic responses. T-cell receptor assembly is a dynamic process that uses the combinatorial diversity of V(D)J recombination to develop a wide-range of antigen recognition (Alcover, Alarcón, & Di Bartolo, 2018). These T-cell receptors use interactions with the thymic epithelium to limit autoimmunity and ensure T-cell viability. In the end, T-cells differentiate into two primary subsets that express the cell surface markers CD4 or CD8 (with constitutive expression of CD3) (Dupage & Bluestone, 2016; Zhang & Bevan, 2011). CD8+ T-cells primarily interact with peptides on major histocompatibility complex (MHC)-I, which is expressed by most cells in the body, and facilitates antigen presentation of intracellular pathogens. CD4+ T-cells interact with peptides on MHC-II, which is expressed by antigen-presenting cells, like macrophages. If a distinct T-cell receptor recognizes the peptide in a MHC assembly then T-cell activation will be initiated (Smith-Garvin, Koretzky, & Jordan, 2009). Along with antigen recognition by the T-cell receptor, T-cell receptor activation requires several co-stimulatory receptors, including CD2, CD4, or CD8, and the integrin lymphocyte function-associated antigen 1 (LFA1). Upon T-cell activation, molecular pathways, including the nuclear factor of activated T-cells (NFAT), promote differentiation of T-cells into effector cells. During this process T-cells proliferate, and a portion of T-cells acquire the ability to traffic to sites of infection, where they can promote local innate immune responses through cytokine production. T-cell subsets use varied mechanisms to eliminate pathogens and kill infected cells. For instance, when CD8+ T-cells identify a cell infected with an intracellular pathogen they use contact-dependent mechanisms to induced apoptosis in the target cell and eventual clearance (Zhang & Bevan, 2011). In contrast, CD4+ T-cells are directed to become T-helper cells, which produce cytokines that can modulate innate immune functions as well as B-cell responses (Dupage & Bluestone, 2016). T-helper cell subsets are distinguished by production of specific cytokines. The CD4+ TH1 subset is characterized by the capacity to make interferon (IFN)-γ‎ and IL-2, which drives activation of monocytes, natural killer cells, and cytolytic T-cell responses. The CD4+ TH2 subset releases the cytokines IL-4, IL-10, and IL-13, which promotes antibody production by B-cells and resolution of innate immune responses. As with most biological systems there is some plasticity in T-helper cell subsets, and other specialized subsets such as TH17 cells that are linked to autoimmunity (Dupage & Bluestone, 2016). The dynamic responsivity of T-cells allows them to identify a wide range of pathogens; however, the limited distribution of T-cells and requirement for antigen presentation delays their responsivity. Upon pathogen elimination the majority of T-cells undergo apoptosis; however, a subset of T-cells are retained with antigen-specific memory. This memory subset of T-cells can provide valuable protection if the same pathogen is encountered again. In all, T-cells are critical mediators of adaptive immune responses and efficiently eliminate pathogens and malignant cells.

B-cells are another subset of lymphocyte, whose main function is to generate antibodies. Unlike T-cells, B-cells develop in the bone marrow from the common lymphocyte progenitor. Similar to T-cells, B-cells use genetic recombination to develop surface receptors for antigens or pathogens (Treanor, 2012). These recombination events create the heavy and light chain portions of the immunoglobulin IgM and IgD isotypes, which will subsequently be tested for self-reactivity to limit autoimmunity. If the B-cell is not self-reactive then it will be released from the bone marrow and will traffic to the spleen or secondary lymphoid tissues. In these immune organs B-cells can further differentiate and produce antigen-specific antibodies through interactions with T-helper cells. In the initial stages of B-cell activation antigen binds to surface immunoglobulins and cross-links the receptors, initiating intracellular signaling that processes the antigen for presentation on MHC-II. In this way, B-cells can contact CD4+ T-cells that are reactive to the specific antigen and have been previously activated by an antigen-presenting cell. This T-cell interaction promotes further differentiation of B-cells into memory cells or plasma cells (Nutt, Hodgkin, Tarlinton, & Corcoran, 2015). These memory B-cells can produce short-lived, low-affinity antibodies or they form germinal centers (De Silva & Klein, 2015). In germinal centers, B-cells undergo significant proliferation and alter antibody production through class-switching, which uses gene rearrangement of the antibody sequences to produce immunoglobulin IgG, IgA, or IgE isotypes. In this process the B-cells can adapt molecular pathways that generate antibodies with higher affinity for specific antigens (De Silva & Klein, 2015). These antibodies have pluripotent effects, including opsonization of toxins, facilitating phagocytosis of pathogens, and tagging pathogens for cell- or complement-mediated lysis (Bonilla & Oettgen, 2010).

Another important immune cell is the natural killer cell, which are large granular lymphocytes that exhibit functions similar to CD8+ T-cells and granulocytes. Natural killer cells are derived from common lymphoid progenitors and differentiate in the bone marrow. Following release from the bone marrow natural killer cells traffic to primary and secondary lymphoid organs and further develop into effector cells (Gregoire et al., 2007). Natural killer cells are early responders to foreign cells and also identify cells infected with pathogens or cells that are transforming into tumors. Natural killer cells primarily recognize MHC-I molecules through cell surface interactions. This is relevant because foreign cells express different MHC-I molecules, and infected or tumor cells can reduce MHC-I expression. Thus, mismatch or absence of MHC-I causes activation of natural killer cells, which release cytolytic granules along with pro-inflammatory cytokines and chemokines to engage innate immune cells. The ability of natural killer cells to effectively identify foreign or dystrophic cells without prior exposure is a unique characteristic that helps defend against chimeric integration of foreign cellular components as well as limiting cancer growth (Moretta, Bottino, Mingari, Biassoni, & Moretta, 2002; Vivier, Nunes, & Vely, 2004).

Interactions Between Innate and Adaptive Immune Systems

Despite different effector cells and functions, the innate and adaptive immune systems have dynamic interactions. Since innate immune cells, particularly granulocytes and macrophages, are the initial responders to infections or tissue damage, their responsivity is generally instructive to the adaptive immune system. Indeed, innate immune cells identify the origin of antigens through PRRs and then can present antigen to T-cells or B-cells, which is critical to induce the appropriate development of effector cells and responses. In particular, PRR sensing of viral infections leads to production of interferons and pro-inflammatory cytokines IL-6 and IL-1β‎, which promote development of CD8+ T-cells that use cytolytic mechanisms to kill virus-infected cells. Further PRR sensing of bacteria promotes release of IL-6, IL-1β‎, and IL-12, leading to development of TH1 cells that drive inflammatory and phagocytosis of pathogens. The example of bacterial infection shows that cytokine release from cells of the innate and adaptive immune systems reciprocally regulate one another. In the end, these dynamic interactions are refined to limit excessive immune reactivity and “immunopathology” (Iwasaki & Medzhitov, 2015).

Autonomic Signals Regulate Development of Immune Cells

Studies on circadian rhythms provided initial evidence that the sympathetic nervous system outflow modulated hematopoiesis, or development of immune cells in the bone marrow. Normal circadian rhythms of sympathetic neuron activity were associated with changes in hematopoietic stem cell proliferation, and could be prevented by β‎-adrenergic receptor antagonists (Maestroni et al., 1998). These neuroimmune interactions were likely mediated directly by sympathetic neurons that project axon terminals in close proximity to immune cell progenitors in the bone marrow (Felten et al., 1985). Moreover, hematopoietic progenitor cells in the bone marrow express adrenergic receptors (Muthu et al., 2007). Other studies show that sympathetic neurons regulate immune cell development under homeostatic conditions and during various challenges, such as stress and inflammation. These challenges increase sympathetic signaling in the bone marrow, which leads to increased norepinephrine levels (Tang, Shankar, Gamelli, & Jones, 1999) and subsequent activation of β‎-adrenergic receptors on immune cell progenitors (Hanke et al., 2012; Tang et al., 2001). This sympathetic signaling in the bone marrow directly regulates hematopoiesis as increased catecholamine release leads to proliferation and motility of immune cell progenitors (Katayama et al., 2006; Spiegel et al., 2007). Rodent studies suggest that sympathetic activation promotes selective enhancement of myeloid cells in the bone marrow. For instance, exposure to social defeat or chronic variable stress increased the proportion of myeloid cells in the bone marrow (Engler, Bailey, Engler, & Sheridan, 2004; Engler, Engler, Bailey, & Sheridan, 2005). In these murine stress models β‎-adrenergic receptor blockade with propranolol or a selective β‎3-receptor antagonist prevented stress-induced enhancement of myeloid lineage cells (Hanke et al., 2012; Heidt et al., 2014). Further studies using social defeat suggest that sympathetic signaling drives myeloid cell expansion through increased GM-CSF expression and increased production of granulocyte and monocyte progenitors in the bone marrow. Notably, expansion of myeloid populations in the bone marrow results in reduced production of lymphocyte progenitors (Powell et al., 2013). There is no anatomical evidence that parasympathetic neurons innervate the bone marrow; therefore it is unlikely that the parasympathetic nervous system directly influences hematopoiesis or initial development of immune cells. Several studies indicate that parasympathetic signals impact immune cell differentiation and reactivity, which will be discussed further elsewhere.

Of note, other studies suggest that chronic stress exposure or inflammation can promote neuroplasticity and remodeling of sympathetic nervous system innervation in immune tissues. Specifically, repeated stress can increase the release and turnover of norepinephrine in the bone marrow (Tang et al., 1999). Other immune organs, such as the lymphoid system, show similar neuronal plasticity with increased sympathetic neuron innervation of lymph nodes following psychological stress (Sloan et al., 2007; Sloan, Capitanio, & Cole, 2008). Other work using rhesus monkeys showed that exposure to social instability increased the density of sympathetic nerve fibers in lymph nodes (Capitanio & Cole, 2015). Further investigation will be needed to determine the immunological and physiological consequences of increased sympathetic input to immune organs.

Autonomic Signals Alter Mobility and Distribution of Immune Cells

Activation of the sympathetic nervous system exerts broad effects on the distribution of immune cells in the blood and peripheral immune organs. The sympathetic nervous system is required for proper hematopoietic stem cell migration and release. In rodent studies pharmacological or genetic disruption of the sympathetic nervous systems caused significant deficits in hematopoietic stem cell egress from the bone marrow and administration of a β‎2-adrenergic receptor agonist increased mobilization of immune cells from the bone marrow (Katayama et al., 2006). Similar findings are reported in clinical studies as human hematopoietic stem cells were shown to express β‎2-adrenergic receptors, and stimulation with catecholamines promoted motility, proliferation, and differentiation of progenitor cells (Spiegel et al., 2007). In addition, acute administration of norepinephrine and epinephrine in rodents caused a significant increase in circulating neutrophils and monocytes (presumably from bone marrow), while corticosterone appeared to direct these cells to immune organs (i.e., spleen) (Dhabhar et al., 2012).

Consistent with these findings, stress models that cause sympathetic activation are often associated with significant redistribution of peripheral immune cells throughout the body (Reader et al., 2015; Wohleb, McKim., Sheridan, & Godbout, 2015). Indeed repeated social defeat in mice increased norepinephrine levels in the bone marrow and promoted release of myeloid lineage immune cells (i.e., granulocytes, monocytes) into circulation (Hanke et al., 2012). These findings are consistent with clinical studies that show high levels of stress in humans was associated with increased circulating neutrophils and inflammatory Ly6Chi monocytes (Heidt et al., 2014). Studies using repeated social defeat or chronic variable stress models revealed key downstream signals that promote release of myeloid-derived immune cells from the bone marrow into circulation. Of note, the chemokine CXCL12 is an important factor that promotes retention of leukocytes in the bone marrow. In the chronic stress models CXCL12 expression was reduced in bone marrow stromal cells, which corresponded with accumulation of myeloid-derived immune cells in the blood. Of note, norepinephrine administration decreased CXCL12 expression in the bone marrow as well. Thus, activation of the sympathetic nervous system contributes to release of myeloid cells from the bone marrow by regulating CXCL12 expression in the bone marrow (Heidt et al., 2014). The increased cycling of myeloid cells in the bone marrow in response to sympathetic activation shifts the phenotype of peripheral monocytes to be less mature and more inflammatory, with increased capacity to traffic throughout the body and promote pro-inflammatory signaling (Geissmann et al., 2010). The implications of this shift in monocyte phenotype will be discussed in the section “Autonomic Signals Promote Molecular Pathways That Alter Immune Cell Reactivity.”

Beyond release of immune cells from the bone marrow, sympathetic activation can influence the distribution of immune cells throughout the body. For instance, increased circulating levels of norepinephrine in the spleen and blood are associated with accumulation of myeloid cells in the spleen following repeated social defeat (Engler et al., 2004; Engler et al., 2005). Additional studies revealed that immune challenge with endotoxin compounded these effects, with exaggerated increases of myeloid cells in the spleen and blood (Wohleb et al., 2012). Similar to other physiological responses induced by the sympathetic nervous system, redistribution of immune cells may be adaptive, enabling the immune system to respond dynamically to homeostatic threats. Indeed these responses may be protective as stress-induced sympathetic activation enhanced leukocyte trafficking to sites of tissue injury (Viswanathan & Dhabhar, 2005) and infection (Dhabhar & McEwen, 1999). Despite these potential advantages, recent work indicates that persistent monocyte redistribution caused by sympathetic activation can have deleterious effects. In a model of atherosclerosis Swirski and colleagues showed that myocardial infarction or stroke caused release of immature monocytes into circulation; this effect was mediated by sympathetic activation and subsequent adrenergic receptor signaling (Dutta et al., 2012). These immature monocytes “seeded” the spleen and provided a sustained influx of monocytes in circulation (Swirski et al., 2009). As a result, spleen-derived monocytes contributed to the ongoing pathophysiology underlying atherosclerosis and increased the risk of secondary myocardial infarction or stroke (Dutta et al., 2012). Other studies show that stress-associated redistribution of primed immune cells promotes inflammatory-related pathology in target organs. For instance, repeated social defeat caused accumulation of neutrophils and monocytes in the lung, which increased expression of pro-inflammatory cytokines in the absence of further immune challenge (Curry et al., 2010). Notably, cholinergic signaling by parasympathetic neurons can indirectly influence leukocyte trafficking by reducing adhesion molecule expression on myeloid cells in the spleen (Huston et al., 2009).

More recent studies indicate that repeated social defeat in mice promotes accumulation of monocyte progenitors in the spleen and sensitized sympathetic responses to subsequent stressors. In particular, acute stress in mice previously exposed to repeated social defeat caused a robust release of monocytes into circulation. These monocytes were derived from the spleen, as splenectomy prevented increased levels of monocytes in circulation (Wohleb et al., 2014). Further studies revealed that release of these monocytes after acute stress was mediated by sympathetic innervation of the spleen (McKim et al., 2016). Stress-associated release of monocytes into circulation is important because monocytes can accumulate in the brain (Wohleb, Powell, Godbout, & Sheridan, 2013), and release of pro-inflammatory cytokines by these monocytes can affect behavior and cognition (Hodes et al., 2014; Menard et al., 2017). Notably, trafficking of monocytes to the brain is not observed in all stress paradigms (Lehmann, Cooper, Maric, & Herkenham, 2016). Altogether these findings indicate that stress-induced trafficking of inflammatory monocytes contributes to the exacerbation of both physical and mental diseases (Liezmann, Stock, & Peters, 2012; Nahrendorf & Swirski, 2015; Wohleb et al., 2015).

Autonomic Signals Promote Molecular Pathways That Alter Immune Cell Reactivity

Binding of adrenergic or cholinergic neurotransmitter receptors on immune cells initiates molecular signaling that has dynamic effects on immune function. Initial experiments using immune cells isolated from the blood revealed that norepinephrine administration caused a dose-dependent reduction in pro-inflammatory cytokines TNF-α‎ and IL-6 after stimulation with lipopolysaccharide. The inhibitory effect of norepinephrine was prevented by the β‎1-adrenergic receptor antagonist metoprolol, but not the α‎-adrenergic receptor antagonist phentolamine. These effects were attributed to intracellular pathways because norepinephrine did not affect the binding of LPS to the cell surface marker CD14 (van der Poll, Jansen, Endert, Sauerwein, & van Deventer, 1994). Other studies using in vivo LPS stimulation in rats showed that acute stress reduced pro-inflammatory cytokine release in the spleen. Sympathetic activation was implicated in this work because ligation of splenic nerves and adrenalectomy prevented the stress-associated reductions in splenic pro-inflammatory cytokine production following LPS stimulation (Meltzer et al., 2004). In contrast to these results comparative studies in humans and rodents showed that acute stress increased catecholamine release that promoted activation of the pro-inflammatory transcription factor NF-κ‎B in peripheral immune cells (Bierhaus et al., 2003). Moreover, the potential pro-inflammatory effects of sympathetic activation influenced immune responses and survival in an experimental sepsis model. In these experiments, the α‎2-adrenergic receptor antagonist attenuated pro-inflammatory cytokine levels and decreased binding activity of NF-κ‎B following cecal ligation and puncture-induced sepsis. These findings showed that decreased sympathetic signaling significantly reduced immune reactivity and mortality in this sepsis model (Hofer et al., 2009). These studies suggest that the magnitude and duration of sympathetic activation influences the impact on immune function.

Persistent activation of the sympathetic nervous system in response to chronic stress is also implicated in driving pro-inflammatory signaling in immune cells. Early clinical studies showed that norepinephrine activated the transcription factor GATA-1 in human macrophages, leading to elevated expression of IL-6. These findings are relevant because 10-year mortality risk was linked to socio-environmental factors and increased IL-6 expression (Cole et al., 2010). Further studies show that the chronic stress of being the primary caregivers of patients with brain cancer was associated with increased expression of genes bearing response elements for NF-κ‎B in peripheral monocytes. Further analyses indicated that the CD14+/CD16- monocyte subset was the primary source of this elevated inflammatory profile. The increased inflammatory phenotype of monocytes in chronically stressed individuals is important because subsequent ex vivo immune stimulation caused increased production of IL-6 (Miller et al., 2014). These studies expounded on prior work that showed caregiver stress is associated with down-regulation of transcriptional activity mediated by the glucocorticoid receptor, resulting in functional glucocorticoid insensitivity and loss of anti-inflammatory regulation in monocytes (Miller et al., 2008).

Molecular changes in immune cells are observed in other chronic stress conditions as well. Comparative analyses of humans and macaques showed that social isolation is associated with expansion of monocytes in the blood and up-regulation of inflammatory-related transcriptional pathways that are modulated by adrenergic receptor signaling (Cole et al., 2015). Early life stress also modulated gene expression in leukocytes, with increased levels of genes with NF-κ‎B binding motifs that were enriched in monocytes. Changes in monocyte gene expression were linked to transcription pathways that are responsive to sympathetic nervous system activation (Cole et al., 2012). Psychological stressors, including the suffering from a mental health disorder, may promote similar pro-inflammatory phenotypes. For instance, higher levels of hostility and severity of depression symptoms were associated with elevated levels of cytokines IL-1β‎, TNFα‎, and IL-8 in circulating monocytes of depressed women (Suarez, Lewis, Krishnan, & Young, 2004). These studies highlight a “conserved transcriptional response to adversity” in leukocytes that is linked to increased sympathetic nervous system signaling and may be a molecular pathway that links chronic stress with inflammation and physical diseases. Interestingly, stress-induced changes in immune cell gene expression are attenuated with cognitive based therapy or improved social interaction (Antoni et al., 2012; Fredrickson et al., 2015).

Rodent models of stress provide further evidence that sympathetic nervous system activation promotes pro-inflammatory changes in immune cells. Myeloid cells in the blood of mice exposed to repeated social defeat exhibited a comparable pro-inflammatory “transcriptional fingerprint” as humans exposed to chronic stress. Importantly, pro-inflammatory changes in myeloid cell gene expression were prevented by β‎-adrenergic receptor antagonism (Powell et al., 2013). Further studies showed functional implications as peripheral myeloid cells isolated from socially defeated mice displayed enhanced pro-inflammatory cytokine expression following immune stimulation of pathogen recognition receptors, TLR2 and TLR4. Moreover, pre-treatment with a β‎-adrenergic receptor antagonist reduced expression of TLR2 and TLR4 on peripheral myeloid cells (Hanke et al., 2012). Following social defeat stress, myeloid cells also displayed glucocorticoid insensitivity, in which they showed reduced cell death following ex vivo glucocorticoid treatment (Avitsur, Stark, & Sheridan, 2001; Bailey, Avitsur, Engler, Padgett, & Sheridan, 2004; Stark et al., 2001). Further evidence indicates that sympathetic activity in other stress paradigms can augment immune cell reactivity and promote inflammatory pathways. In particular, studies using inescapable tail shock stress revealed that increased pro-inflammatory cytokines (IL-1β‎ and IL-6) in circulation were blocked by α‎1- and β‎-adrenergic receptor antagonism (Johnson et al., 2005b). Alterations in these pro-inflammatory cytokines were associated with elevated levels of heat shock protein (Hsp)-72 in circulation, which acts as a DAMP to stimulate immune cells. In these studies stress-induced increases in circulating Hsp-72 were blocked by α‎1-adrenergic receptor antagonism and without prior stress α‎1-adrenergic receptor agonists increased Hsp-72 in the circulation (Johnson et al., 2005a).

Stress-induced molecular changes in myeloid cells have functional implications. Enhanced pro-inflammatory cytokine production and release of reactive oxygen species following immune stimulation enhanced the ability of splenic macrophages to kill bacteria (Allen et al., 2012; Bailey, Engler, Powell, Padgett, & Sheridan, 2007). These “immunogenic” myeloid cells also promoted adaptive immune responses to influenza virus infection by increasing the number of CD8+ T-cells, which reduced the viral expression in the lungs (Powell, Mays, Bailey, Hanke, & Sheridan, 2011). Importantly, this sympathetic-mediated alterations in myeloid cell function can cause aberrant tissue damage (Mays et al., 2010), and exaggerated inflammation in stressed or aged mice is associated with protracted depressive-like behaviors and cognitive impairments (Kinsey, Bailey, Sheridan, & Padgett, 2008; Sparkman & Johnson, 2008; Wohleb et al., 2012).

Beyond the innate immune system and inflammation, studies show that sympathetic nervous system release of norepinephrine can influence T-cell effector populations. Sanders and colleagues showed that the TH1 subset of effector T-cells preferentially expressed the β‎2-adrenergic receptor. This restricted neurotransmitter receptor expression enabled norepinephrine to selectively modulate function of TH1, but not TH2 cells. In these studies norepinephrine administration decreased TH1 cell production of IL-2, but did not affect IFN-γ‎ levels (Ramer-Quinn, Baker, & Sanders, 1997). Further studies showed that norepinephrine stimulation of β‎2-adrenergic receptor on naïve CD4+ T-cells promoted differentiation of TH1 effector cells with significantly higher expression of IFN-γ‎ (Swanson, Lee, & Sanders, 2001). It is plausible that these selective T-cell responses to norepinephrine contribute to enhanced T-cell memory function and elevated production of IFN-γ‎ by CD4+ T-cells in socially defeated mice exposed to influenza infection (Mays et al., 2010). There is limited research on how sympathetic-mediated changes in T-cell function affect B-cell development or antibody production. Of note, recent studies show that B-cells promote inflammatory responses in an arthritis model through production of antibodies that target collagen. B-cells were shown to express β‎2-adrenergic receptor and norepinephrine attenuated B-cell production of collagen-specific antibodies (Pongratz et al., 2014).

The parasympathetic nervous system via release of acetylcholine also modulates immune reactivity. Acetylcholine regulates inflammation by binding α‎7-nicotinic acetylcholine receptors on macrophages, which blocked release of TNFα‎, IL-1β‎, and IL-6, but not IL-10, after immune stimulation. Moreover, direct electrical stimulation of the vagus nerve attenuated TNFα‎ levels in the serum and prevented development of shock following high doses of endotoxin (Borovikova et al., 2000; Wang et al., 2003). Direct administration of acetylcholine or the specific agonist nicotine prevented release of the DAMP signaling protein HMGB1 by macrophages following endotoxin stimulation, which was linked with decreased HMGB1 levels in the blood and improved survival in an experimental sepsis model (Wang et al., 2004). Similarly, electrical stimulation of the vagus nerve in vivo reduced HMGB1 levels and increased survivability after high dose endotoxin (Huston et al., 2007). The spleen may be a critical mediator of these effects as ablation of the splenic nerve attenuated the anti-inflammatory effects of cholinergic agonists (Rosas-Ballina et al., 2008). Indeed splenic nerve stimulation was sufficient to recapitulate the anti-inflammatory effects of vagus nerve stimulation or cholinergic agonists (Vida, Pena, Deitch, & Ulloa, 2011). In separate studies splenectomy reduced HMGB1 levels and prevented mortality after high dose endotoxin (Huston et al., 2008). This rapid immunomodulatory effect of the vagus nerve was integrated into a pathway called the “cholinergic anti-inflammatory reflex” (Tracey, 2009). In the afferent connection it is proposed that vagus nerve endings expressing IL-1 receptors and chemosensory cells in proximity to vagus nerve endings signal to the brain that an inflammatory response is mounting (Goehler et al., 2000).

The specific mechanisms by which the parasympathetic nervous system exerts anti-inflammatory effects remain unclear because there is no clear anatomical evidence that cholinergic neurons innervate immune organs (Nance & Sanders, 2007). Ongoing studies have aimed to define cellular mediators of the cholinergic anti-inflammatory reflex. Compelling studies showed that the anti-inflammatory effect of vagus nerve stimulation was prevented in mice lacking β‎2-adrenergic receptors or T-lymphocytes. Further experiments showed that β‎2-adrenergic receptor signaling on a subset of T-cells in the spleen is required for the anti-inflammatory effects of vagus nerve stimulation. These data indicate that the vagus nerve utilizes sympathetic neurons in the anti-inflammatory reflex, which is plausible as sympathetic nerve terminals directly appose T-cells in the spleen (Bellinger & Lorton, 2014). Elaborating on these findings, Tracey and colleagues showed that vagus nerve stimulation caused sympathetic neuron release of norepinephrine that signaled to CD4+ T-cells in the spleen. Following β‎2-adrenergic receptor activation these splenic T-cells, in turn, released acetylcholine that binds to acetylcholine receptors on proximal macrophages, leading to diminished TNFα‎ production (Rosas-Ballina et al., 2011). Consistent with these findings, separate studies showed that adoptive transfer of CD4+ T-cells restored the anti-inflammatory potential of vagus nerve stimulation in immunocompromised and septic mice (Pena et al., 2011).

Conclusions

The research outlined here demonstrates that the autonomic nervous system has an important role in modulating immune cell development, distribution, and reactivity. Postganglionic neurons from the sympathetic nervous system send axon terminals into immune organs enabling direct regulation of immune function. Neurons from the parasympathetic nervous system do not directly innervate immune organs; however, they can utilize sympathetic connections to influence immune functions as well. In varied contexts, sympathetic or parasympathetic activation can engage molecular mechanisms that drive adaptations in immune cell function. The discovery of these neuroimmune pathways generated an expansive area of research. Future studies will need to expound on this work to understand how these dynamic neuroimmune pathways shape immune function in varied contexts, including physiological or psychological challenges, and how autonomic nervous systems can be utilized to treat disease.

Suggested Reading

Ben-Shaanan, T. L., Azulay-Debby, H., Dubovik, T., Starosvetsky, E., Korin, B., Schiller, M., . . . Rolls, A. (2016). Activation of the reward system boosts innate and adaptive immunity. Nature Medicine 22, 940–944.Find this resource:

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