AUTNEU-01631; No of Pages 3 Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx

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Autonomic nervous system and inflammation☆ Keywords: Inflammation Immune system Autonomic nervous systems Central nervous system Host defense Health Disease

Trauma leading to tissue injury, invasion of microbes and infection activates the inflammatory pathway that consists of inducers, sensors, mediators and effectors of inflammation (Medzhitov, 2008, 2010). Broken cells, microbes and their products and neuropeptides released by terminals of nociceptive primary afferent neurons are sensed by sentinel cells located in the injured tissue such as mast cells, macrophages and dendritic cells. These cells release many substances that turn on and mediate the “molecular machinery” of the immune system and activate several other effectors, such as endothelial cells and vascular smooth muscle cells resulting in the full development of inflammation. This inflammatory process involves the recruitment of different groups of immune cells such as neutrophils, antigen-presenting cells and lymphocytes releasing a host of substances that amplify inflammation and vascular endothelia, platelets and coagulation factors. The inflammatory response needs to develop as quickly as possible to terminate the spread of infection, to limit further tissue injury and to protect the host. This process is organized by a molecular program that actively coordinates the action and interaction of the different cellular components that are geared in their intensity by the input signals produced by the tissue injury and the invading microbes. This initial fast developing inflammatory reaction resolves quickly once the tissue has been cleared of microbes and their toxins and of other detrimental consequences of the injury following cell necrosis. The resolution of the inflammation is also an active process orchestrated by a molecular working program that involves more or less the same cells of the immune system and associated cells. The development and resolution of inflammation are finely tuned to each other according to the size of tissue injury to avoid a too early resolution of inflammation and subsequent expansion of microbes and their toxins in the body on one side and to prevent an uncontrolled prolongation of inflammation developing into chronic inflammation on the other (Nathan, 2002; Serhan and Savill, 2005; Medzhitov, 2008; Nathan and Ding, 2010). At the defense lines of the body (skin, mucosa of the gastrointestinal tract, mucosa of the respiratory tract, mucosa of the pelvic organs), low-

☆ Acknowledgements: The research was supported by the German Research Foundation. I thank Elspeth McLachlan and Hans-Georg Schaible for their comments.

grade inflammation and low-grade anti-inflammatory processes proceed continuously. Thus we have as human–microbial consortia so-to-speak a “basal inflammatory tone” and a “basal anti-inflammatory tone” that are in equilibrium; the first protects us under physiological conditions against potentially invading microbes and the second against uncontrolled dysregulation of inflammation. Disturbance of this equilibrium results in disease. The power of the resolution mechanisms of inflammation is dependent on close to 100 gene products. Loss-of-function mutation of one of these genes, e.g. produced experimentally in mice, results in persistent inflammation in normal living conditions (Nathan and Ding, 2010). In autoimmune disorders, such as rheumatoid arthritis, the molecular programs of starting and resolving inflammation may be continuously active under sterile conditions independent of the inducers (microbes, damaged cell products). Under physiological conditions, the inflammatory–anti-inflammatory defense system seems to function independent of the central nervous system (CNS) although the CNS is mobilized during noxious stimuli that activate primary afferent nociceptive neurons and the central nociceptive system. This triggers the activation of various protective body reactions, mediated by the autonomic nervous system, the somatomotor system and neuroendocrine systems, including macroscopic protective body behaviors. Does the CNS interfere with the inflammatory and antiinflammatory defensive processes occurring in the body tissues? It is commonly believed that the CNS is able to control inflammatory processes in the body, and in this context the immune system, implying that it can assist healing of injured tissues or trigger the opposite, e.g. under adverse signals from the CNS, leading to diseases of the body. Furthermore, it is commonly believed that the CNS is important in maintaining health of the body as indicated by concepts hiding behind the term “psychoneuroimmunology” (see Ader, 2007). The CNS and the immune system communicate reciprocally with each other. The afferent communication occurs via primary afferent nociceptive neurons, which innervate practically all body tissues, and by cytokines secreted by immune cells in the inflamed tissues or in the secondary lymphoid organs. The efferent communication occurs via the peripheral autonomic (largely sympathetic) nervous system (Nance and Sanders, 2007) and neuroendocrine systems (e.g., the hypothalamopituitary-adrenal system and possibly the sympatho-adrenal system). The peripheral sympathetic nervous system is organized in several anatomically and functionally distinct channels according to the target organs (Jänig this issue, Jänig, 2006; Mathias and Bannister, 2013). Thus, what is the nature of this efferent communication from the CNS to the immune tissue? Does it occur via a functionally distinct sympathetic channel or a group of functionally distinct sympathetic channels or are all sympathetic noradrenergic pathways including the sympathoadrenal system involved in this communication? Where in the cellular complexity of the immune tissue and inflammatory pathway does the peripheral sympathetic nervous system interact with adrenoceptors? 1566-0702/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Jänig, W., Autonomic nervous system and inflammation, Auton. Neurosci. (2014), j.autneu.2014.02.002



After all, practically all cells of the immune tissue express β2- and/or α1adrenoceptors (Bellinger and Lorton, this issue). These basic questions are linked to the question as to which central circuits in spinal cord, brain stem and hypothalamus, all of them presumably being under cortical control, are involved in the regulation of activity in the sympathetic pathway(s) supplying the immune tissues? Unraveling this hypothetical central neural machinery linked to the sympathetic pathway(s) involved in regulation of the immune system and inflammation will ultimately further our knowledge about the neural mechanisms presumed to be vital for health and well-being. This knowledge should open the avenue to optimize therapeutic (non-invasive and nonpharmacological) interventions exerted centrally and/or at the superficial and deep body tissues in treating functional diseases involving the immune system (Mayer and Bushnell, 2009; King et al., 2011). This Special Issue of Autonomic Neuroscience concentrates on the efferent autonomic communication from the brain to the immune system and therefore on the question in which way and to what degree are inflammatory processes in the body modulated via the (efferent) autonomic nervous system by the CNS. This question is largely unanswered. We must discriminate various aspects of this question: (1) The cellular, anatomical and physiological organization of the autonomic nervous system and of the immune system (primary and secondary lymphoid tissues); (2) the modulation of the cellular processes in the primary and secondary lymphoid tissues by the sympathetic innervation; (3) the modulation of inflammation in body tissues by the sympathetic innervation; (4) the distinction between local and systemic effects of the modulation by the sympathetic nervous system; (5) the modulation of acute and of chronic inflammation by the sympathetic nervous system and therefore the distinction between physiology and pathophysiology; (6) pro- and anti-inflammatory effects of the sympathetic nervous system; and (7) research on the communication from the sympathetic postganglionic neurons to the immune cells in the primary and secondary lymphoid tissues and in inflamed tissues obtained in vitro must be translated into the in vivo situation. Bellinger and Lorton describe the potential cellular and subcellular tools by way of which the noradrenergic sympathetic postganglionic neurons communicate with the immune tissues. They give an overview about the anatomy of the sympathetic innervation of the immune tissues, about the regulation and differentiation of the different types of immune cells by the sympathetic innervation, the β2- and α1-adrenoceptors involved and the intracellular pathways coupled to them. They clearly argue and conclude that there is no direct parasympathetic innervation of immune tissues. This does not collide with the observation that parasympathetic neurons may be involved in the regulation of the mucosal immunity. They critically discuss that we need in vivo experimentation to find out which of the cellular and subcellular pathways in the sympathetic– immune-tissue communication are used in the in vivo regulation of the immune tissue by the CNS. Martelli and co-workers critically discuss the neurobiological basis of the cholinergic (vagal) anti-inflammatory pathway being potentially involved in the control of local and systemic inflammation that has been worked out and propagated by Kevin Tracey and his group (for references see Martelli et al.). This pathway can be activated by electrical stimulation of the vagus nerve or pharmacologically. However, it is unlikely to be the efferent pathway of inflammatory reflex responses of the immune tissue (e.g., the spleen) to endotoxemia. This efferent arm is the sympathetic innervation (Martelli et al., 2014). Four contributions discuss the role of the autonomic system in the regulation of the mucosal immunity of the respiratory tract (McGovern and Mazzone), the gastrointestinal tract (Cervi and co-workers, Sharkey and Savidge) and the urothelium (Birder). The autonomic innervation is involved in regulation of blood flow, motility and secretion, barrier function of the mucosa and function of the immune systems associated with these organs. To hypothesize and speculate, at these mucosal barriers there exist a continuous inflammatory and anti-inflammatory tone (see above, Nathan and Ding, 2010) involving immune cells, the efferent

autonomic innervation (sympathetic, parasympathetic, enteric) and the pepdidergic afferent innervation. These body surfaces are continuously exposed to microbes, potentially toxic compounds and also exposed to mechanical stress. How are the different neural, endocrine, humoral, paracrine and immune signals integrated in the host defense functions at these barriers? Two contributions discuss the role of the sympathetic innervation in the development of acute and chronic (sterile) inflammation of the rat knee joint. Using the acute model of bradykinin-induced synovial plasma extravasation Jänig and Green show that this plasma extravasation largely depends on the sympathetic innervation, but not on activity in the sympathetic neurons and not on release of norepinephrine, that the plasma extravasation is under inhibitory control of nociceptive–neuroendocrine reflex pathways the efferent arms being the sympathoadrenal system and the hypothalamo-pituitary-adrenal system, and that these nociceptive–neuroendocrine reflex pathways are under powerful inhibitory control of vagal afferent neurons innervating the small intestines. An idea about the spinal and spino-bulbar-spinal pathways orchestrating the regulation of the synovia via the sympatho-adrenal system has been worked out. The cellular and molecular mechanisms underlying the change of vascular permeability dependent on the sympathetic innervation is unknown. Schaible and Straub show that the sympathetic innervation of the synovia of the rat knee joint influences powerfully the experimental inflammation in addition to the control of synovial blood flow. Using chemical sympathectomy or blockade of adrenoceptors they show that activity in the sympathetic neurons enhances joint inflammation in the acute phase and reduces joint inflammation in the chronic phase. This correlates with the observation that the density of the sympathetic innervation of the synovial tissue decreases chronically during inflammation. They conclude that we are just at the beginning to understand the non-vasoconstrictor function of the sympathetic innervation of the synovia under healthy and inflamed conditions. In fact both groups of investigators show that the sympathetic nervous system (including the sympatho-adrenal system) is involved by multiple mechanisms in synovial inflammation. McLachlan and Hu have studied the invasion of macrophages and T-lymphocytes into dorsal root ganglia (DRG) containing axotomized afferent neurons following peripheral nerve injury as a model of a sterile inflammation. They show that this invasion of immune cells into the DRG is partly dependent on the activity in the sympathetic innervation of the DRG. Surprisingly, some of the enhancement of this invasion of immune cells seems to be mediated by β2-adrenoceptors; activation of α1-adrenoceptors depresses the invasion. These results are perplexing and important since it is believed that ectopic activity in injured primary afferent neurons leading potentially to neuropathic pain also depends on cytokines released by immune cells which in turn may be enhanced by norepinephrine released by sympathetic postganglionic neurons. Complex regional pain syndrome (CRPS) is a pain disease that may show prominent signs of inflammation in somatic tissues that are hypothesized to be dependent on the sympathetic innervation. Schlereth and coworkers argue, based on quantitative measurements conducted on CRPS patients, that the inflammation is maintained by norepinephrine released by sympathetic postganglionic neurons activating cells of the immune system and enhancing the production of cytokines in the affected tissues. They hypothesize that this process is involved in the development of inflammation as well as nociceptor sensitization in the CRPS patients. In conclusion, the contributions to this Special Issue of Autonomic Neuroscience clearly show that we are moving in a highly interesting and entirely open territory of future research. This includes the fields of immunology, inflammation, autonomic nervous system, nociception and pain, control of protective body reactions orchestrated by the CNS, and regulation of organ functions under physiological and pathophysiological conditions. We need to look at the topic Autonomic Nervous System and Inflammation in an integrative way that includes these

Please cite this article as: Jänig, W., Autonomic nervous system and inflammation, Auton. Neurosci. (2014), j.autneu.2014.02.002


different fields. This will enable us to ask the right questions and formulate testable hypotheses for experimentation in vivo. References Ader, A. (Ed.), 2007. Fourth edition. Psychoneuroimmunology, volume 1 and 2. Academic Press Elsevier, Amsterdam. Jänig, W., 2006. The Integrative Action of the Autonomic Nervous System: Neurobiology of Homeostasis. Cambridge University Press, Cambridge, New York. King, H.H., Jänig, W., Patterson, M.H. (Eds.), 2011. The Science and Clinical Application of Manual Therapy. Churchill Livingstone Elsevier, Edinburgh. Martelli, D., Yao, S.T., McKinley, M.J., McAllen, R.M., 2014. Reflex control of inflammation by sympathetic nerves, not the vagus. J. Physiol. (in press). Mathias, C.J., Bannister, R. (Eds.), 2013. Autonomic Failure, Fifth edition. Oxford University Press, New York Oxford. Mayer, E.M., Bushnell, M.C. (Eds.), 2009. Functional Pain Syndromes: Presentation and Pathophysiology. IASP Press, Seattle. Medzhitov, R., 2008. Origin and physiological roles of inflammation. Nature 454, 428–435.


Medzhitov, R., 2010. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776. Nance, D.M., Sanders, V.M., 2007. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav. Immun. 21, 736–745. Nathan, C., 2002. Points of control in inflammation. Nature 420, 846–852. Nathan, C., Ding, A., 2010. Nonresolving inflammation. Cell 140, 871–882. Serhan, C.N., Savill, J., 2005. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197.

Wilfrid Jänig Physiologisches Institut, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany Tel.: +49 431 880 2036; fax: +49 431 880 4580. E-mail address: [email protected]. 29 January 2014 Available online xxxx

Please cite this article as: Jänig, W., Autonomic nervous system and inflammation, Auton. Neurosci. (2014), j.autneu.2014.02.002

Autonomic nervous system and inflammation.

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