Denise L. Bellinger

Noradrenergic Sympathetic Neural Interactions with the Immune System: Structure and Function

Histochemical studies from our (Williams & Felten 1981, Williams et al. 1981, D. Felten et al. 1981, 1984, 1985, 1987a, 1987b, Livnat et al. 1985, Ackerman et al. 1986, S. Felten et al. 1987) and other laboratories (Giron et al. 1980, Bulloch & Pomeranz, 1984, Singh 1984, Walcott & MacLean 1985) have shown the presence of autonomic nerve fibers in specific compartments of both primary and secondary lymphoid organs. These nerve fibers are associated not only with blood vessels but also with lymphocytes and macrophages. We have demonstrated that the neurotransmitter norepinephrine (NE), present in the postganglionic sympathetic fibers that richly innervate lymphoid organs, acts in the spleen as both a paracrine secretion, available to receptors on cells in the white pulp, and a localized neurotransmitter in nerve terminals that directly contact T lymphocytes in the periarteriolar lymphatic sheath (PALS) (S. Felten et al. 1986, S. Felten & Olschowka 1987). We propose that NE in lymphoid organs fulfills the criteria for neurotransmission, estabUshed in more traditional efTector tissues such as the heart, and plays a role in the modulation of immune responses. This review summarizes evidence for neurotransmission, including presence and compartmentation of NE, transmitter release, post-synaptic receptors on cells of the immune system, and functional consequences of denervation and pharmacological manipulation of NE. We also review aspects of development, aging, and plasticity of noradrenergic (NA) fibers that enhance our understanding of their role in organs of the immune system.

Sympathetic innervation of lymph nodes in mice

Noradrenergic innervation of popliteal and mesenteric lymph nodes in mice was examined with fluorescence histochemistry. Dense varicose plexuses entered the nodes with the vasculature in the hilar region and continued with the vasculature into the medullary region. Fine, delicate varicosities and small vascular plexuses continued into the cortical and paracortical regions surrounding the germinal centers; some varicosities ended among lymphocytes. A subcapsular plexus contributed fibers into the cortical and paracortical regions. Chemical measurements revealed the presence of norepinephrine in lymph nodes that was depletable with 6-hydroxydopamine. Depletion of norepinephrine from lymph nodes with this agent resulted in a diminished primary immune response in draining lymph nodes following subcutaneous injection of an antigen in two mouse strains, but had no effect in two other strains. These findings suggest that noradrenergic fibers innervate both the vasculature and parenchymal regions of lymph nodes, and may participate in the modulation of immune responses in these organs.

The significance of vasoactive intestinal polypeptide (VIP) in immunomodulation.

Evidence for VIP influences on immune function comes from studies demonstrating VIP-ir nerves in lymphoid organs in intimate anatomical association with elements of the immune system, the presence of high-affinity receptors for VIP, and functional studies where VIP influences a variety of immune responses. Anatomical studies that examine the relationship between VIP-containing nerves and subpopulations of immune effector cells provide evidence for potential target cells. Additionally, the presence of VIP in cells of the immune system that also possess VIP receptors implies an autocrine function for VIP. The functional significance of VIP effects on the immune system lies in its ability to help coordinate a complex array of cellular and subcellular events, including events that occur in lymphoid compartments, and in musculature and intramural blood circulation. Clearly, from the work described in this chapter, the modulatory role of VIP in immune regulation is not well understood. The pathways through which VIP can exert an immunoregulatory role are complex and highly sensitive to physiological conditions, emphasizing the importance of in vivo studies. Intracellular events following activation of VIP receptors also are not well elucidated. There is additional evidence to suggest that some of the effects of VIP on cells of the immune system are not mediated through binding of VIP to its receptor. Despite our lack of knowledge regarding VIP immune regulation, the evidence is overwhelming that VIP can interact directly with lymphocytes and accessory cells, resulting in most cases, but not always in cAMP generation within these cells, and a subsequent cascade of intracellular events that alter effector cell function. VIP appears to modulate maturation of specific populations of effector cells, T cell recognition, antibody production, and homing capabilities. These effects of VIP are tissue-specific and are probably dependent on the resident cell populations within the lymphoid tissue and the surrounding microenvironment. Different microenvironments within the same lymphoid tissue may influence the modulatory role of VIP also. Effects of VIP on immune function may result from indirect effects on secretory cells, endothelial cells, and smooth muscle cells in blood vessels, ducts, and respiratory airways. Influences of VIP on immune function also may vary depending on the presence of other signal molecules, such that VIP alone will have no effect on a target cell by itself, but may greatly potentiate or inhibit the effects of other hormones, transmitters, or cytokines. The activational state of target cells may influence VIP receptor expression in these cells, and therefore, may determine whether VIP can influence target cell activity. Several reports described in this chapter also indicate that VIP contained in neural compartments is involved in the pathophysiology of several disease states in the gut and lung. Release of inflammatory mediators by cells of the immune system may destroy VIP-containing nerves in inflammatory bowel disease and in asthma. Loss of VIPergic nerves in these disease states appears to further exacerbate the inflammatory response. These studies indicate that altered VIP concentration can have significant consequences in terms of health and disease. In addition, the protective effects of VIP from tissue damage associated with inflammatory processes described in the lung also may be applicable to other pathological conditions such as rheumatoid arthritis, anaphylaxis, and the swelling and edema seen in the brain following head trauma. While VIP degrades rapidly, synthetic VIP-like drugs may be developed that interact with VIP receptors and have similar protective effects. Synthetic VIP-like agents also may be useful in treating neuroendocrine disorders associated with dysregulation of the hypothalamic-pituitary-adrenal axis, and pituitary release of prolactin.

Innervation of lymphoid organs and implications in development, aging, and autoimmunity

We now have substantial evidence demonstrating noradrenergic sympathetic and peptidergic innervation of both primary and secondary lymphoid organs. We have established criteria for norepinephrine, and some of the neuropeptides, as neurotransmitters, and have found changes in immune responsiveness following pharmacological manipulation of noradrenergic sympathetic or peptidergic nerves. Classic receptor binding studies have demonstrated a wide variety of target cells that possess beta-adrenoceptors and receptors for neuropeptides on cells of the immune system, including lymphocyte subsets, macrophages, accessory cells, or stromal elements. In this chapter we describe noradrenergic and peptidergic innervation of primary and secondary lymphoid organs in development, at maturation and during the normal aging process, and discuss possible functional implications of direct neural signals onto cells of the immune system at critical time points in the lifespan of an animal. Further, we examine for involvement of noradrenergic sympathetic and peptidergic innervation in the development and progression of several autoimmune disorders, including adjuvant-induced arthritis, New Zealand mice strains as a model for hemolytic anemia and lupus-like syndrome, and the experimental allergic encephalomyelitis model for multiple sclerosis.

Acetylcholinesterase staining and choline acetyltransferase activity in the young adult rat spleen: lack of evidence for cholinergic innervation.

Acetylcholinesterase (AChE) staining in spleens from young adult Sprague-Dawley rats was examined following several denervation paradigms to determine the source of splenic AChE+ nerve fibers. In spleens from all control groups, AChE+ neural-like profiles were present along the vasculature and in the trabeculae. AChE+ reactivity also was present in lymphoid and reticular cells in the spleen, and in neuronal cell bodies in the superior mesenteric-coeliac ganglion (SM-CG). Neurochemical analysis revealed no significant choline acetyltransferase activity in spleens from control animals. Surgical removal of the SM-CG resulted in a total loss of both noradrenergic (NA) and AChE+ nerve profiles, as well as a loss of AChE staining in nonneural compartment in the spleen. On Days 1 and 3 after treatment, chemical sympathectomy with 6-hydroxydopamine also resulted in a loss of both NA and AChE nerve profiles in the spleen, except for a few resistant fibers in the hilar region. AChE reactivity in nonneural compartments also was diminished in chemically denervated regions of the spleen. AChE staining in both neural and nonneural profiles progressively increased from 10 to 56 days after chemical sympathectomy, with a time course and distribution pattern similar to NA fibers reinnervating the spleen. AChE+ staining was preserved following bilateral vagal nerve transection. The miniscule splenic levels of choline acetyltransferase suggest that at best, only a small density of cholinergic nerves distribute to the rat spleen. Further, what cholinergic innervation is present does not arise from the vagus nerve as suggested in the earlier literature. Collectively, the overlapping distribution of AChE+ and NA nerve profiles in spleen and parallel loss of both population of nerve fibers following surgical and chemical sympathectomy support the presence of AChE in NA nerves colocalized with norepinephrine, and thus make AChE+ staining an inappropriate marker for cholinergic innervation in the rat spleen.

Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep.

This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1β and tumor necrosis factor-α, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system’s ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep.

Ontogeny and Senescence of Noradrenergic Innervation of the Rodent Thymus and Spleen

Publisher Summary This chapter explores the ontogeny, maturation, and senescence of noradrenergic (NA) sympathetic neurotransmission in two lymphoid organs. Noradrenergic sympathetic nerves provide an anatomical link between the nervous and immune systems throughout the life span of the host. Developmental and age-related changes in NA neurotransmission are complex and continuous, varying with each organ of the immune system. In the rat thymus, a primary lymphoid organ, NA innervation was predominantly vascular during early development, and peak density of innervation was not achieved until after thymic involution. The chapter presents a study in which NA innervation was maintained in some aged rodents and increased in density in the thymus as a result of thymic involution. In contrast, NA innervation of spleen and lymph nodes declined with age, in parallel with a loss of lymphocytes and macrophages from these organs. Noradrenergic neurotransmission is dependent not only on the presence of nerve fibers in appropriate compartments of target organs but also on the rate of release of transmitter, the concentration of transmitter in the vicinity of target cells, the presence of functional receptors, and the ability of target cells to respond to NA signals.

Autonomic regulation of cellular immune function.

The nervous system and the immune system (IS) are two integrative systems that work together to detect threats and provide host defense, and to maintain/restore homeostasis. Cross-talk between the nervous system and the IS is vital for health and well-being. One of the major neural pathways responsible for regulating host defense against injury and foreign antigens and pathogens is the sympathetic nervous system (SNS). Stimulation of adrenergic receptors (ARs) on immune cells regulates immune cell development, survival, proliferative capacity, circulation, trafficking for immune surveillance and recruitment, and directs the cell surface expression of molecules and cytokine production important for cell-to-cell interactions necessary for a coordinated immune response. Finally, AR stimulation of effector immune cells regulates the activational state of immune cells and modulates their functional capacity. This review focuses on our current understanding of the role of the SNS in regulating host defense and immune homeostasis. SNS regulation of IS functioning is a critical link to the development and exacerbation of chronic immune-mediated diseases. However, there are many mechanisms that need to be further unraveled in order to develop sound treatment strategies that act on neural-immune interaction to resolve or prevent chronic inflammatory diseases, and to improve health and quality of life.

Retracted: Maternal and early life stress effects on immune function: relevance to immunotoxicology

RETRACTED

Decreased sympathetic innervation of spleen in aged Fischer 344 rats.

Splenic noradrenergic innervation in young adult and aged Fischer 344 rats was examined using fluorescence histochemistry for catecholamines and high performance liquid chromatography with electrochemical detection (LCEC) for the quantitation of norepinephrine (NE). In young adult rats, abundant noradrenergic plexuses followed the vasculature and trabeculae into splenic white pulp. In aged rats, noradrenergic innervation was reduced in density and in overall intensity of fluorescence, and splenic NE levels were significantly lower. The relationship between diminished noradrenergic innervation and diminished immune responsiveness in aging mammals, while not clear on a causal level, is presented as a hypothesis for further testing.