Autonomic-mediated immunomodulation and potential clinical relevance

α7nAChR= : α7 subunit-containing nicotinic receptor; ACh= : acetylcholine; ACTH= : adrenocorticotrophic hormone; β 2AR ; cAMP= : cyclic adenosine monophosphate; CRH= : corticotropin-releasing hormone; Epi= : epinephrine; IFN= : interferon gamma; IL-1= : interleukin IL-1 beta; IL-1R= : interleukin-1 receptor; MS= : multiple sclerosis; NE= : norepinephrine; NFκB= : nuclear factor kappa B; NPY= : neuropeptide Y; NTS= : nucleus of the solitary tract; PgE2= : prostaglandin E2; PVN= : paraventricular nucleus; RVLM= : rostral ventrolateral medulla; TNF= : tumor necrosis factor-alpha. There is an active bidirectional communication between the immune system and the nervous system. Cytokines released from immune cells provide signals to neurons of the hypothalamus and brainstem, which trigger endocrine and autonomic responses that, in turn, inhibit the immune response. Both the sympathetic and the vagal efferent pathways participate in this anti-inflammatory and immunosuppressant action. Neurally mediated immunosuppression is adaptive and limits the extent of local or systemic inflammation. However, when activated in the setting of acute stroke or other forms of CNS injury, this response may lead to profound downregulation of both innate and adaptive immunity and predispose to infections, which are a major cause of morbidity and mortality in these patients. There are several excellent reviews focused on the various mechanisms involved in brain-immune interactions1–7 and more recent publications focus on the consequences of immunodeficiency triggered by CNS injury.8,9 Some relevant concepts on mechanisms and effect of autonomic activation on immune responses and the potential clinical implications are reviewed here. Macrophages and monocytes respond to various stimuli by releasing proinflammatory cytokines, including tumor necrosis factor-alpha (TNFα), interleukin (IL)-1 beta (IL-1β), IL-6, IL-12, and interferon gamma (IFNγ); these mediators are both effectors of inflammation and signal molecules to the nervous system. There are at least 2 pathways by which the brain senses inflammation: a neural pathway and a humoral pathway (figure 1).2 Figure 1 Immune signaling to the CNS Proinflammatory cytokines, including interleukin (IL)-1β, released during inflammation provide signals to the CNS via neural and humoral pathways. IL-1β or other proinflammatory cytokines activate vagal afferents that terminate in the nucleus of the solitary tract. Ascending projections from this nucleus or from catecholaminergic A1/C1 cells located in the ventrolateral medulla reach the hypothalamus, including the paraventricular nucleus. Circulating proinflammatory cytokines may also enter the brain …