The interplay between the autonomic and immune systems

Given the growing evidence and interest in immune system-to-brain and brain-to-immune system signalling, we proposed a symposium on this topic in the context of autonomic nervous system regulation at the International Society for Neuroscience meeting, which was held in Buzios, Brazil, 12–16 September 2011. Here, we describe briefly our motivation for this exciting topic and summarize a number of papers that were presented at the symposium. Some years ago, we discovered leucocytes that were adhered to the microvasculature of the brainstem of the spontaneously hypertensive rat but not normotensive animals (Waki et al. 2007). We imagined that these cells could affect ongoing endogenous physiological signalling across the blood–brain barrier or that they could release molecules capable of affecting neuronal behaviour or extravasate to affect neuronal function. It was also likely that these immune cells could clog vessels, causing hypoperfusion and thereby exacerbating any immune response. Whether this could alter autonomic function was unknown at the time. We subsequently tested it. By expressing an adhesion molecule (junctional adhesion molecule-A) within the nucleus tractus solitarii of normotensive rats, leucocytes became attracted to the microvasculature and this generated hypertension (Waki et al. 2007). This evidence supported the idea that hypertension was, in part, based on direct interactions between the innate immune system acting within the brain (Xu et al. 2012). Other studies have reported activation of microglial cells in the paraventricular nucleus of the hypothalamus in animals treated with infusions of angiotensin II (Shi et al. 2010). Thus, evidence exists that immune cells can extravasate into the brain to form microglia that directly affect neuronal function, regulating the autonomic nervous system in disease states. Indeed, T-cell activation occurs after angiotensin II infusion and appears necessary for much of the hypertension that follows (Marvar et al. 2010). Thus, there is an intimate relationship between the immune system and autonomic motor activity. Recently, it has come to light that while the immune system interacts directly within brain regions that regulate autonomic function, the autonomic nervous system innervates organs that contain immune cells, such as the spleen and bone marrow (e.g. Zubcevic et al. 2011; Abboud et al. 2012). Indeed, effects on immune cells of both the parasympathetic and the sympathetic nervous system have been described (Rosas-Ballina et al. 2011). Moreover, both cholinergic receptors and adrenoceptors exist on immune cells and provide the substrate for their modulation (activation or inactivation) by nervous and hormonal mechanisms. Based on the fascinating bidirectional communication between the immune and autonomic regulatory systems, we proposed a symposium at the International Society for Autonomic Neuroscience meeting 2011. What follows is a brief synopsis of the papers that were presented at our sympoisum, which was entitled Autonomic Neuro-Immunomodulation: the Interplay between Two Integrative Systems – Nervous and Immune Systems, as well as additional related papers. Many T cells originate in the thymus. Migration of T cells within the thymus and ultimately from this organ into the bloodstream is a highly regulated process. Dr W. Savino described mechanisms by which thymic T-cell migration occurs that involve semaphorin 3A and its receptor, neuropilin 1, which are constitutively expressed by thymocytes (Mendes-da-Cruz et al. 2012). Activation of neuropilin 1 receptors by semaphorin 3A decreases adhesion of thymocytes to thymic epithelial cells and can inhibit chemoattractant processes mediated by a number of other molecules. The case was articulated for a significant role for semaphorin 3A in the control of T-cell migration into the circulation. Whether this molecule is modulated by the autonomic nervous system is not clear, but it would provide a mechanism through which T cells could become activated and delivered by the autonomic nervous system. Dr P. Marvar presented data on the role of the adaptive immune system and T cells in the development of angiotensin II-induced hypertension, as well as the resulting end-organ damage (Marvar & Harrison, 2012). Factors described that contribute to T-cell involvement in hypertension were the high blood pressure itself and psychological stress. Marvar & Harrison (2012) explain how stress-induced cardiovascular changes are associated with the activation of T cells, which affect central nervous autonomic circuits that regulate arterial pressure. Exactly when in the process of development of hypertension the T cells become important remains unclear, but it is unlikely, according to Marvar & Harrison (2012), that this is the initiating step. In addition to hypertension being associated with changes in the innate immune system, there are other diseases including heart failure (see above) and Chagas disease. This can be life-threatening causing cardiac arrhythmias and sudden death. Chagas disease is caused by an infection from the parasite Trypanosoma cruzi (Machado & Dias da Silva, 2012). In a murine model of Chagasic cardiomyopathy, Machado et al., (2012) report that Chagas disease results in inflammatory infiltration within the heart which is associated with its autonomic dysfunction. Using a combination of transgenic mice with altered autonomic nerve activity (depressed parasympathetic or depressed cardiac sympathetic activity) and conventional autonomic pharmacology, the authors found a profound role for the autonomic nervous system in both suppression of the immune system and reduction of the rate of parasite clearance in the murine model of Chagas disease. The interaction between the autonomic nervous system and clearance of the parasite is interesting; whether this effect is mediated by the immune system is important to confirm, because there could then be general applicability to other parasite-mediated diseases. Whilst it appears that angiotensin II can activate T cells and that the sympathetic nervous system innervates organs containing immune cells, such as the spleen and bone marrow, it has become less clear whether parasympathetic fibres also control the immune response through innervation of organs that regulate immune cells. Tracey and colleagues have demonstrated that there is evidence for nicotinic receptors on immune cells within the spleen, supporting the possibility for innervation by the parasympathetic nervous system (Rosas-Ballina et al. 2011). Stimulation of the vagus nerve can suppress inflammation that is dependent on the spleen and splenic nerves. As the vagus does not innervate the spleen, Bratton et al. (2012) undertook a study to assess whether a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons exists. However, using neuroanatomical tract tracing and electrophysiological techniques, Bratton et al. (2012) report no evidence of such a connection. It is therefore unclear how the nicotinic receptors on immune cells are activated, unless from locally released or circulating acetylcholine. In this themed issue of Experimental Physiology, additional papers are included that were not presented within the symposium but that are relevant to the autonomic–immune topic (Benrick et al. 2012; Iannitti et al. 2012; May et al. 2012; O’Connor et al. 2012; Pilipovićet al. 2012).