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Bellocchi, C. The Autonomic Nervous System Interaction with Immunity. Encyclopedia. Available online: (accessed on 02 March 2024).
Bellocchi C. The Autonomic Nervous System Interaction with Immunity. Encyclopedia. Available at: Accessed March 02, 2024.
Bellocchi, Chiara. "The Autonomic Nervous System Interaction with Immunity" Encyclopedia, (accessed March 02, 2024).
Bellocchi, C. (2022, March 04). The Autonomic Nervous System Interaction with Immunity. In Encyclopedia.
Bellocchi, Chiara. "The Autonomic Nervous System Interaction with Immunity." Encyclopedia. Web. 04 March, 2022.
The Autonomic Nervous System Interaction with Immunity

The autonomic nervous system (ANS) and the immune system are deeply interrelated. The ANS regulates both innate and adaptive immunity through the sympathetic and parasympathetic branches, and an imbalance in this system can determine an altered inflammatory response as typically observed in chronic conditions such as systemic autoimmune diseases. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis all show a dysfunction of the ANS that is mutually related to the increase in inflammation and cardiovascular risk. Moreover, an interaction between ANS and the gut microbiota has direct effects on inflammation homeostasis. Recently vagal stimulation techniques have emerged as an unprecedented possibility to reduce ANS dysfunction, especially in chronic diseases characterized by pain and a decreased quality of life as well as in chronic inflammation.

nervous systems autonomic nervous system gut microbiota inflammation innate immunity adaptive immunity

1. Introduction

The autonomic nervous system (ANS) has two main components, the sympathetic and the parasympathetic branches, that dynamically regulate the visceral functions [1]. Previous and recent findings are confirming the strong reciprocal interrelation between ANS and the immune system. Since ANS can regulate inflammation in chronic and acute conditions, autonomic dysfunction can have a pivotal influence on the onset and progression of many diseases where the immune response is involved, such as autoimmune diseases [2][3][4]

2. Autonomic Nervous System and Innate Immunity

The immune system is a complex interplay between immune cells, receptors, and self and non-self peptides. Innate immunity is the first response to microbes where pattern recognition receptors (PRRs) elicit the activation of immune/inflammatory processes after recognition of conserved pathogen-associated molecular patterns (PAMPs) that are present on bacteria, viruses, and fungi [5] or towards damage- (or danger-) associated molecular patterns (DAMPs) and others. Among PRRs, Toll-like receptors (TLRs), nod-like receptors, C-type lectin receptors, and many others have a role in inducing innate immune responses; when PRRs are present on antigen-presenting cells, mainly dendritic cells (DCs), they can induce also the adaptive immune response [6]. Furthermore, DCs play a pivotal role in contributing to either immune activation or maintaining the immune tolerance that is crucial to preventing autoimmunity [7][8]. Defensins, complement, granulocytes, and natural killer (NK) cells are components of innate immunity, determining inflammation that initially has a protective role from external or internal agents that have to be removed [5][9].
A deep interaction between the immune system and the nervous system is nowadays well documented and, in particular, innate immunity contributes to the development of the central nervous system (CNS) through microglia cells that are the main innate immune cells present in the brain [10][11]. TLRs are expressed on microglia surface responding to pathogenic or damaging insults [12][13][14]. Furthermore, immune cells and innate immune cells maintain the functioning and homeostasis of the nervous system and an imbalance of this equilibrium, due for example to chronic inflammation, can cause a severe impairment with consequent alteration of cognitive functions [15].
The interaction with innate immunity is not a prerogative of the CNS only and evidence show how the peripheral nervous system and more in specific the ANS have a deep interface with immune cells [16]. Anatomically, the sympathetic branch of ANS is present in immunological organs such as the thymus, spleen bone marrow, and lymph nodes while of interest, no evident traces of the parasympathetic fibers have been demonstrated [16][17][18][19][20][21][22]. Moreover, immune cells present adrenergic receptors able to bind norepinephrine that confers the ability to crosstalk with the sympathetic nerves, namely the alpha-adrenergic receptor (αAR) and the beta-adrenergic receptor (βAR), the latter more expressed on innate immune cells [23][24]. The receptors αAR and βAR have effects in opposite directions, where αAR can be considered more stimulatory, while βAR is inhibitory, and under homeostatic conditions, βAR has an overall predominant effect [25]. Altogether, from several studies, norepinephrine inhibits cytokines production, namely TNFα when expressed from monocytes, macrophage, and microglia in response to the lipopolysaccharide (LPS) constituent of the bacterial cell-wall as well as inhibits IL-1β or IL-6 production [26][27][28][29][30]. Norepinephrine has a direct effect on innate immune cells, increasing circulating NKs and granulocytes [31][32][33]. Neutrophil chemotaxis and phagocytosis are negatively regulated from norepinephrine; the NK function impairment after stroke seems to be mediated by a noradrenergic neurotransmitter, and the NK response is suppressed by catecholamines [34][35][36][37][38][39][40]. The βAR mediated effect of catecholamines suppress macrophage functions including their cytokine production [41][42]. Overall, the activation of the sympathetic nervous system attenuates the innate immunity as also demonstrated in a randomized control trial on human healthy subjects [43].
The parasympathetic branch that includes the vagus nerve has several effects on the innate immune system through the interaction between receptors present on the cellular surface and neurotransmitters, namely acetylcholine [44]. This communication is bidirectional and happens despite the fact that anatomically the parasympathetic fibers have not been individuated in the main immunologic organs such as the spleen and thymus [16][22]. Through vagal afferent fibers, the message that inflammation is present in other body sites reaches the CNS, as demonstrated by animal models of vagotomy in which the lack of vagal contribution determines reduced central responses with a blunted increase in body temperature and cortisol production [45][46][47]. Evidence of how the vagal afferents are activated by inflammation is not yet completely clear, but it has been suggested that IL-1β receptors, present especially in the vagal paraganglia, are the main promotors of this afferent reflex to the CNS; moreover, IL-1β is itself a key contributor in the direct stimulation of the brain to activate the inflammatory cascade [48][49].
The vagus nerve has an anti-inflammatory effect through the release of acetylcholine, mainly through the interaction with the α7 nicotinic acetylcholine receptor (α7nAChR) present on macrophages [50]. On cultures of LPS-stimulated human macrophages, acetylcholine attenuates the production of TNF, as well as of IL-6 and IL-1β, but not of the anti-inflammatory cytokine IL-10 [51]. The spleen is one of the main targets of vagal action towards the immune system. Indeed, it has been demonstrated how vagal stimulation reduces TNF macrophage production in mice sepsis models [52]. Due to the lack of parasympathetic fibers in the spleen, it has been hypothesized that the innervation is provided by catecholaminergic fibers from the celiac-superior mesenteric plexus ganglia that are under the control of preganglionic neurons of the thoracic spinal cord gray column [19][53][54][55]. Recently, an electrophysiological study performed on rats excluded the presence of a direct vagal-splenic nerve connection supporting the hypothesis of an effect towards splenic nerves mediated by vagal afferences through the CNS [21][33]. This neuronal modulation of inflammation through vagal afferences and efferences has been termed the “inflammatory reflex” [56]. Overall, the inflammatory reflex is crucial to maintain homeostasis with a balance between pro and anti-inflammatory responses as evident by the increase in morbidity and mortality during sepsis when a vagal depression is present [57][58][59][60].

3. Autonomic Nervous System and Adaptive Immunity

Adaptive immunity is the specialized branch of immunity able to respond to specific pathogens and to maintain an immunological memory over time. The main cells involved are lymphocytes B and T. The sympathetic nervous system is able to regulate the mobilization of lymphocytes in the bloodstream through catecholamines that directly interact with β2AR present on the lymphocytes’ surface [61]. Moreover, β2AR is selectively expressed on naïve T cells, CD4+ T helper (Th) 1, and regulatory T cells (Tregs) and induces T helper differentiation towards a Th1 phenotype through IFNγ/IL-12 interaction in in vitro studies, while in in vivo the Th differentiation is orchestrated via DCs+ [62][63]. Norepinephrine has an inhibitory effect on cytotoxic CD8+ T cells and modulates Tregs [64][65][66]. Regarding B cells, catecholamines have an indirect effect on their maturation and on antibodies production through their action on T cells that are necessary as costimulation in the B mediated immune responses [63]. Evidence on a direct effect of β2AR on B cells is limited; a lack of norepinephrine prevents a normal expression of IgG in mice [67] and norepinephrine induces β2AR mediated CD86 expression (a costimulator) on B cells [68][69].
Vagal stimulation increases acetylcholine release in the spleen and suppresses TNF-α in control BALB/c mice models of endotoxemia, while it does not reduce TNF-α in nude mice, suggesting that T cells are involved in the inflammatory reflex and that a T cell deficiency impairs the inflammatory reflex [70]. Moreover, α7nAChR present in T cells also causes a decrease in adhesion molecules expression and lymphocyte proliferation and both nicotinic and muscarinic acetylcholine receptors are present in lymphocytes that regulate their activities producing acetylcholine in a paracrine/autocrine control [71][72]. The role of vagal stimulation in increasing acetylcholine with beneficial effects on inflammation has been recently suggested also in the postural orthostatic tachycardia syndrome (POTS). POTS is a condition characterized by an impairment of the neuromodulation and consequent dysautonomia. Different studies showed a role of autoantibodies in POTS suggesting an autoimmune mediated pathogenesis of this condition [73][74]. In a recent study on a rabbit model of POTS induced by M2 muscarinic acetylcholine receptor-activating autoantibodies immunization, transcutaneous vagus nerve stimulation contributes to increasing acetylcholine with consequent reduction in both inflammation and cardiovagal dysfunction [75].
Overall, once the inflammatory reflex is activated, the sympathetic and parasympathetic branches of ANS act synergistically instead of oppositely as intuitively expected Figure 1. Indeed, as elegantly depicted by Tracey [56], this synergic contribution implies that the vagal afferent fibers signal to the CNS (mainly within the nucleus of tractus solitarius) the presence of peripheric inflammatory/infective stimulus (intercepted for cytokines release and/or pathogens presence), and in response, vagal efferent fibers suppress cytokine release through nicotinic receptors present on macrophages, and throughout the cholinergic anti-inflammatory pathway. At the same time, the pain caused by the ongoing inflammatory processes can activate the sympathetic branches through the flight-or-fight responses determining norepinephrine release and consequent suppression of inflammation (via the pathways already detailed above) [76][77].
Figure 1. Sympathetic and parasympathetic synergic function on the innate and adaptive immunity.
It is important to add that these mechanisms can have different implications and functioning in acute versus chronic conditions, as described in acute stress that can cause an immune hyperactivation, while chronic stress is typically associated with an immunosuppressive status [78], and what keeps the homeostasis is the dynamic balance between all these regulatory systems; when one system is prevailing, the imbalance can cause, or be the consequence of, a pathological condition, such as for example, chronic autoimmune diseases [79]. Finally, by way of example of the deep bidirectional complex interactions between the nervous system and both innate and adaptive immunity, researchers could considered the case of celiac disease (CD) in which evidence shows how both innate and adaptive immunity mechanisms are involved [80]. A wide range of neurological disorders, ANS dysfunction included, mediated by antineuronal and antigangliosides autoantibodies have been indeed demonstrated in CD [81][82][83][84].

4. Autonomic Nervous System and Gut Microbiota

The gastrointestinal tract (GIT) is considered one of the most extended and important immunological organs because of its enormous abundance of cells of both innate and adaptive immunity residing in the bowel mucosa [85]. In the GIT, the immune system directly interacts with the unique microbiota ecosystems that are hosted there; microbiota includes the whole composition of bacteria, fungi, and viruses that are present in a specific body site, and the gut microbiota has a crucial role from birth, allowing the evolution and development of the immune system as demonstrated by germ-free mice models in which the absence of microbiota is associated with an absent or impaired immune development [86][87][88][89]. Moreover, GIT microbiota can regulate the immune interaction with external antigens and maintain the immune homeostasis through its protolerogenic commensal Phyla of bacteria able to metabolize and generate short-chain fatty acids (butyrate, propionate, and acetate) that induce Tregs expansion in the colon [90][91]. A reduction in pro-tolerogenic bacteria, mainly Firmicutes and Bacteroides has been extensively described in studies performed on mice models and in patients with inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) as well as in systemic autoimmune diseases [92][93][94][95].
The brain–gut axis (BGA) is a well-known interaction between the enteric nervous system (ENS) and CNS that also occurs through the sympathetic and parasympathetic branches of ANS [96][97]. Gut microbiota can directly interact with the ENS and indirectly modulate the BGA through neuroendocrine and neuroimmune pathways, all together considered the “brain–gut–microbiota” axis [98][99]. If these mechanisms undergo a dysfunction, an imbalance of this system leads to clinical alteration of the GIT especially with IBS development [100][101][102]. Moreover, the microbiota is directly associated with mental health disorders as demonstrated in knock-out mice models in which the absence of intestinal microbiota influences the development of behavior, along with neurochemical changes in the brain [102][103]. Microbiota alterations can modulate both the brain functions and the ANS through the vagus nerve, sending signals to the CNS and vice versa [104][105][106][107]. A recent study on beta 1 and 2 adrenergic receptor knock-out mice shows that the overall sympathetic reduction increases protolerogenic bacteria, with reduction in circulating CD4+ T cells and reduced IL-17 [108].


  1. Sanvictores, T.; Tadi, P. Neuroanatomy, Autonomic Nervous System Visceral Afferent Fibers and Pain; StatPearls Publishing LLC: Treasure Island, FL, USA, 2022.
  2. Koopman, F.A.; Van Maanen, M.A.; Vervoordeldonk, M.J.; Tak, P.P. Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J. Intern. Med. 2017, 282, 64–75.
  3. Thanou, A.; Stavrakis, S.; Dyer, J.W.; Munroe, M.E.; James, J.A.; Merrill, J.T. Impact of heart rate variability, a marker for cardiac health, on lupus disease activity. Arthritis Res. Ther. 2016, 18, 197.
  4. Gigante, A.; Rosato, E.; Liberatori, M.; Barbano, B.; Cianci, R.; Gasperini, M.; Sardo, L.; Marra, A.; Amoroso, A.; Salsano, F.; et al. Autonomic dysfunction in patients with systemic sclerosis: Correlation with intrarenal arterial stiffness. Int. J. Cardiol. 2014, 177, 578–580.
  5. Takeuchi, O.; Akira, S. Pattern Recognition Receptors and Inflammation. Cell 2010, 140, 805–820.
  6. Iwasaki, A.; Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 2015, 16, 343–353.
  7. Shortman, K.; Caux, C. Dendritic Cell Development: Multiple Pathways to Nature’s Adjuvants. Stem Cells 1997, 15, 409–419.
  8. Banchereau, J.; Steinman, R.M. Dendritic cells and the control of immunity. Nature 1998, 392, 245–252.
  9. Nathan, C. Points of control in inflammation. Nature 2002, 420, 846–852.
  10. Korin, B.; Ben-Shaanan, T.L.; Schiller, M.; Dubovik, T.; Azulay-Debby, H.; Boshnak, N.T.; Koren, T.; Rolls, A. High-dimensional, single-cell characterization of the brain’s immune compartment. Nat. Neurosci. 2017, 20, 1300–1309.
  11. Matcovitch-Natan, O.; Winter, D.R.; Giladi, A.; Aguilar, S.V.; Spinrad, A.; Sarrazin, S.; Ben-Yehuda, H.; David, E.; González, F.Z.; Perrin, P.; et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 2016, 353, aad8670.
  12. Olson, J.K.; Miller, S.D. Microglia Initiate Central Nervous System Innate and Adaptive Immune Responses through Multiple TLRs. J. Immunol. 2004, 173, 3916–3924.
  13. Tang, S.-C.; Arumugam, T.V.; Xu, X.; Cheng, A.; Mughal, M.R.; Jo, D.-G.; Lathia, J.D.; Siler, D.A.; Chigurupati, S.; Ouyang, X.; et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc. Natl. Acad. Sci. USA 2007, 104, 13798–13803.
  14. Klein, M.; Obermaier, B.; Angele, B.; Pfister, H.; Wagner, H.; Koedel, U.; Kirschning, C.J. Innate Immunity to Pneumococcal Infection of the Central Nervous System Depends on Toll-Like Receptor (TLR) 2 and TLR4. J. Infect. Dis. 2008, 198, 1028–1036.
  15. Zengeler, K.E.; Lukens, J.R. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nat. Rev. Immunol. 2021, 21, 454–468.
  16. Nance, D.M.; Sanders, V.M. Autonomic innervation and regulation of the immune system (1987–2007). Brain, Behav. Immun. 2007, 21, 736–745.
  17. Romeo, H.E.; Fink, T.; Yanaihara, N.; Weihe, E. Distribution and relative proportions of neuropeptide Y- and proenkephalin-containing noradrenergic neurones in rat superior cervical ganglion: Separate projections to submaxillary lymph nodes. Peptides 1994, 15, 1479–1487.
  18. Trotter, R.N.; Stornetta, R.L.; Guyenet, P.G.; Roberts, M.R. Transneuronal mapping of the CNS network controlling sympathetic outflow to the rat thymus. Auton. Neurosci. 2007, 131, 9–20.
  19. Cano, G.; Sved, A.F.; Rinaman, L.; Rabin, B.S.; Card, J.P. Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing. J. Comp. Neurol. 2001, 439, 1–18.
  20. Bulay, O.; Mlrvish, S.S.; Pelfrene, A.F.; Eagen, M.; Garcia, H.; Gold, B. Carcinogenicity Test of Six Nitrosamides and a Nitrosocyanamide Administered Orally to Rats2. JNCI: J. Natl. Cancer Inst. 1979, 62, 1523–1528.
  21. Bratton, B.O.; Martelli, D.; McKinley, M.J.; Trevaks, D.; Anderson, C.R.; McAllen, R.M. Neural regulation of inflammation: No neural connection from the vagus to splenic sympathetic neurons. Exp. Physiol. 2012, 97, 1180–1185.
  22. Bellinger, D.; Lorton, D.; Hamill, R.; Felten, S.; Felten, D. Acetylcholinesterase Staining and Choline Acetyltransferase Activity in the Young Adult Rat Spleen: Lack of Evidence for Cholinergic Innervation. Brain, Behav. Immun. 1993, 7, 191–204.
  23. Sanders, V.M.; Straub, R.H. Norepinephrine, the β-Adrenergic Receptor, and Immunity. Brain, Behav. Immun. 2002, 16, 290–332.
  24. Sanders, V.M.; E Munson, A. Norepinephrine and the antibody response. Pharmacol. Rev. 1985, 37, 229–248.
  25. Daaka, Y.; Luttrell, L.; Lefkowitz, R.J. Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A. Nature 1997, 390, 88–91.
  26. Meltzer, J.C.; MacNeil, B.J.; Sanders, V.; Pylypas, S.; Jansen, A.H.; Greenberg, A.H.; Nance, D.M. Stress-induced suppression of in vivo splenic cytokine production in the rat by neural and hormonal mechanisms. Brain, Behav. Immun. 2004, 18, 262–273.
  27. Ignatowski, T.; Gallant, S.; Spengler, R.N. Temporal regulation by adrenergic receptor stimulation of macrophage (MΦ)-derived tumor necrosis factor (TNF) production post-LPS challenge. J. Neuroimmunol. 1996, 65, 107–117.
  28. Hetier, E.; Ayala, J.; Bousseau, A.; Prochiantz, A. Modulation of interleukin-1 and tumor necrosis factor expression by ?-adrenergic agonists in mouse ameboid microglial cells. Exp. Brain Res. 1991, 86.
  29. van der Poll, T.; Jansen, J.; Endert, E.; Sauerwein, H.P.; van Deventer, S.J. Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood. Infect. Immun. 1994, 62, 2046–2050.
  30. Severn, A.; Rapson, N.T.; A Hunter, C.; Liew, F.Y. Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists. J. Immunol. 1992, 148.
  31. A Ottaway, C. Central nervous system influences on lymphocyte migration. Brain, Behav. Immun. 1992, 6, 97–116.
  32. Benschop, R.J.; Rodriguez-Feuerhahn, M.; Schedlowski, M. Catecholamine-Induced Leukocytosis: Early Observations, Current Research, and Future Directions. Brain Behav. Immun. 1996, 10, 77–91.
  33. Bellinger, D.L.; Lorton, D. Autonomic regulation of cellular immune function. Auton. Neurosci. 2014, 182, 15–41.
  34. Nicholls, A.J.; Wen, S.W.; Hall, P.; Hickey, M.; Wong, C.H.Y. Activation of the sympathetic nervous system modulates neutrophil function. J. Leukoc. Biol. 2017, 103, 295–309.
  35. Harvath, L.; Robbins, J.D.; A Russell, A.; Seamon, K.B. cAMP and human neutrophil chemotaxis. Elevation of cAMP differentially affects chemotactic responsiveness. J. Immunol. 1991, 146, 224–232.
  36. Zurier, R.B.; Weissmann, G.; Hoffstein, S.; Kammerman, S.; Tai, H.H. Mechanisms of Lysosomal Enzyme Release from Human Leukocytes II. EFFECTS OF cAMP AND cGMP, AUTONOMIC AGONISTS, AND AGENTS WHICH AFFECT MICROTUBULE FUNCTION. J. Clin. Investig. 1974, 53, 297–309.
  37. Wong, C.H.Y.; Jenne, C.N.; Lee, W.-Y.; Léger, C.; Kubes, P. Functional Innervation of Hepatic iNKT Cells Is Immunosuppressive Following Stroke. Science 2011, 334, 101–105.
  38. Irwin, M. Stress-induced immune suppression: Role of brain corticotropin releasing hormone and autonomic nervous system mechanisms. Adv. Neuroimmunol. 1994, 4, 29–47.
  39. Elenkov, I.J.; Wilder, R.L.; Chrousos, G.P.; Vizi, E.S. The sympathetic nerve--an integrative interface between two supersystems: The brain and the immune system. Pharmacol. Rev. 2000, 52, 595–638.
  40. Shakhar, G.; Ben-Eliyahu, S. In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J. Immunol. 1998, 160, 3251–3258.
  41. Suberville, S.; Bellocq, A.; Fouqueray, B.; Philippe, C.; Lantz, O.; Perez, J.; Baud, L. Regulation of interleukin-10 production by β-adrenergic agonists. Eur. J. Immunol. 1996, 26, 2601–2605.
  42. Németh, Z.H.; Szabó, C.; Haskó, G.; Salzman, A.L.; Vizi, E. Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages. Eur. J. Pharmacol. 1997, 339, 215–221.
  43. Kox, M.; van Eijk, L.T.; Zwaag, J.; Wildenberg, J.V.D.; Sweep, F.; van der Hoeven, J.G.; Pickkers, P. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proc. Natl. Acad. Sci. USA 2014, 111, 7379–7384.
  44. Kox, M.; Pickkers, P. Modulation of the Innate Immune Response through the Vagus Nerve. Nephron Exp. Nephrol. 2015, 131, 79–84.
  45. Gaykema, R.P.; Dijkstra, I.; Tilders, F.J. Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology 1995, 136, 4717–4720.
  46. Fleshner, M.; Goehler, L.; Schwartz, B.; McGorry, M.; Martin, D.; Maier, S.; Watkins, L. Thermogenic and corticosterone responses to intravenous cytokines (IL-1β and TNF-α) are attenuated by subdiaphragmatic vagotomy. J. Neuroimmunol. 1998, 86, 134–141.
  47. Huston, J.M.; Ochani, M.; Rosas-Ballina, M.; Liao, H.; Ochani, K.; Pavlov, V.; Puerta, M.; Ashok, M.; Czura, C.J.; Foxwell, B.; et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 2006, 203, 1623–1628.
  48. Goehler, L.E.; Relton, J.K.; Dripps, D.; Kiechle, R.; Tartaglia, N.; Maier, S.F.; Watkins, L.R. Vagal Paraganglia Bind Biotinylated Interleukin-1 Receptor Antagonist: A Possible Mechanism for Immune-to-Brain Communication. Brain Res. Bull. 1997, 43, 357–364.
  49. van Westerloo, D.J. The vagal immune reflex: A blessing from above. Wien. Med. Wochenschr. 2010, 160, 112–117.
  50. Wang, H.; Yu, M.; Ochani, M.; Amella, C.A.; Tanovic, M.; Susarla, S.; Li, J.H.; Wang, H.; Yang, H.; Ulloa, L.; et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 2003, 421, 384–388.
  51. Borovikova, L.V.; Ivanova, S.; Zhang, M.; Yang, H.; Botchkina, G.I.; Watkins, L.R.; Wang, H.; Abumrad, N.; Eaton, J.W.; Tracey, K.J. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000, 405, 458–462.
  52. Rosas-Ballina, M.; Ochani, M.; Parrish, W.R.; Ochani, K.; Harris, Y.T.; Huston, J.M.; Chavan, S.; Tracey, K.J. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl. Acad. Sci. USA 2008, 105, 11008–11013.
  53. Nance, D.M.; Burns, J. Innervation of the spleen in the rat: Evidence for absence of afferent innervation. Brain Behav. Immun. 1989, 3, 281–290.
  54. Hosoi, T.; Okuma, Y.; Matsuda, T.; Nomura, Y. Novel pathway for LPS-induced afferent vagus nerve activation: Possible role of nodose ganglion. Auton. Neurosci. 2005, 120, 104–107.
  55. Vida, G.; Peña, G.; Deitch, E.A.; Ulloa, L. α7-Cholinergic Receptor Mediates Vagal Induction of Splenic Norepinephrine. J. Immunol. 2011, 186, 4340–4346.
  56. Tracey, K.J. The inflammatory reflex. Nature 2002, 420, 853–859.
  57. Pontet, J.; Contreras, P.; Curbelo, A.; Medina, J.; Noveri, S.; Bentancourt, S.; Migliaro, E.R. Heart rate variability as early marker of multiple organ dysfunction syndrome in septic patients. J. Crit. Care 2003, 18, 156–163.
  58. Pavlov, V.A.; Ochani, M.; Yang, L.-H.; Gallowitsch-Puerta, M.; Ochani, K.; Lin, X.; Levi, J.; Parrish, W.R.; Rosas-Ballina, M.; Czura, C.J.; et al. Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis*. Crit. Care Med. 2007, 35, 1139–1144.
  59. Koh, D.-R.; Fung-Leung, W.-P.; Ho, A.; Gray, D.; Acha-Orbea, H.; Mak, T.-W. Less Mortality but More Relapses in Experimental Allergic Encephalomyelitis in CD8 -/- Mice. Science 1992, 256, 1210–1213.
  60. Bernik, T.R.; Friedman, S.G.; Ochani, M.; DiRaimo, R.; Susarla, S.; Czura, C.J.; Tracey, K.J. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J. Vasc. Surg. 2002, 36, 1231–1236.
  61. Dimitrov, S.; Lange, T.; Born, J. Selective Mobilization of Cytotoxic Leukocytes by Epinephrine. J. Immunol. 2009, 184, 503–511.
  62. Guereschi, M.G.; Araujo, L.P.; Maricato, J.T.; Takenaka, M.C.; Nascimento, V.M.; Vivanco, B.C.; Reis, V.O.; Keller, A.C.; Brum, P.C.; Basso, A.S. Beta2-adrenergic receptor signaling in CD4+Foxp3+regulatory T cells enhances their suppressive function in a PKA-dependent manner. Eur. J. Immunol. 2013, 43, 1001–1012.
  63. Sanders, V.M. The beta2-adrenergic receptor on T and B lymphocytes: Do we understand it yet? Brain, Behav. Immun. 2012, 26, 195–200.
  64. Wirth, T.; Westendorf, A.M.; Bloemker, D.; Wildmann, J.; Engler, H.; Mollerus, S.; Wadwa, M.; Schäfer, M.K.-H.; Schedlowski, M.; del Rey, A. The sympathetic nervous system modulates CD4+Foxp3+ regulatory T cells via noradrenaline-dependent apoptosis in a murine model of lymphoproliferative disease. Brain, Behav. Immun. 2014, 38, 100–110.
  65. Kalinichenko, V.V.; Mokyr, M.B.; Graf, L.H.; Cohen, R.L.; A Chambers, D. Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression. J. Immunol. 1999, 163, 2492–2499.
  66. Livnat, S.; Madden, K.S.; Felten, D.L.; Felten, S.Y. Regulation of the immune system by sympathetic neural mechanisms. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1987, 11, 145–152.
  67. Kohm, A.P.; Sanders, V.M. Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo. J. Immunol. 1999, 162, 5299–5308.
  68. Kohm, A.P.; Mozaffarian, A.; Sanders, V.M. B Cell Receptor- and β2-Adrenergic Receptor-Induced Regulation of B7-2 (CD86) Expression in B Cells. J. Immunol. 2002, 168, 6314–6322.
  69. Kasprowicz, D.J.; Kohm, A.P.; Berton, M.T.; Chruscinski, A.J.; Sharpe, A.H.; Sanders, V.M. Stimulation of the B Cell Receptor, CD86 (B7-2), and the β2-Adrenergic Receptor Intrinsically Modulates the Level of IgG1 and IgE Produced per B Cell. J. Immunol. 2000, 165, 680–690.
  70. Rosas-Ballina, M.; Olofsson, P.S.; Ochani, M.; Valdés-Ferrer, S.I.; Levine, Y.A.; Reardon, C.; Tusche, M.W.; Pavlov, V.A.; Andersson, U.; Chavan, S.; et al. Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit. Science 2011, 334, 98–101.
  71. Geng, Y.; Savage, S.; Johnson, L.; Seagrave, J.; Sopori, M. Effects of Nicotine on the Immune Response. I. Chronic Exposure to Nicotine Impairs Antigen Receptor-Mediated Signal Transduction in Lymphocytes. Toxicol. Appl. Pharmacol. 1995, 135, 268–278.
  72. Kawashima, K. Extraneuronal cholinergic system in lymphocytes. Pharmacol. Ther. 2000, 86, 29–48.
  73. Vernino, S.; Stiles, L.E. Autoimmunity in postural orthostatic tachycardia syndrome: Current understanding. Auton. Neurosci. 2018, 215, 78–82.
  74. Li, H.; Yu, X.; Liles, C.; Khan, M.; Vanderlinde-Wood, M.; Galloway, A.; Zillner, C.; Benbrook, A.; Reim, S.; Collier, D.; et al. Autoimmune Basis for Postural Tachycardia Syndrome. J. Am. Hear. Assoc. 2014, 3, e000755.
  75. Deng, J.; Li, H.; Guo, Y.; Zhang, G.; Fischer, H.; Stavrakis, S.; Yu, X. Transcutaneous vagus nerve stimulation attenuates autoantibody-mediated cardiovagal dysfunction and inflammation in a rabbit model of postural tachycardia syndrome. J. Interv. Card. Electrophysiol. 2022, 1–10.
  76. Molina, P.E. Noradrenergic inhibition of TNF upregulation in hemorrhagic shock. Neuroimmunomodulation 2001, 9, 125–133.
  77. Woiciechowsky, C.; Asadullah, K.; Nestler, D.; Eberhardt, B.; Platzer, C.; Schöning, B.; Glöckner, F.; Lanksch, W.R.; Volk, H.-D.; Döcke, W.-D. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat. Med. 1998, 4, 808–813.
  78. Dhabhar, F.S. Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection versus Immunopathology. Allergy, Asthma Clin. Immunol. 2008, 4, 2–11.
  79. Pongratz, G.; Straub, R.H. The sympathetic nervous response in inflammation. Arthritis Res. Ther. 2014, 16, 1–12.
  80. Voisine, J.; Abadie, V. Interplay between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease. Front. Immunol. 2021, 12.
  81. Cervio, E.; Volta, U.; Verri, M.; Boschi, F.; Pastoris, O.; Granito, A.; Barbara, G.; Parisi, C.; Felicani, C.; Tonini, M.; et al. Sera of Patients With Celiac Disease and Neurologic Disorders Evoke a Mitochondrial-Dependent Apoptosis In Vitro. Gastroenterology 2007, 133, 195–206.
  82. Volta, U.; De Giorgio, R.; Granito, A.; Stanghellini, V.; Barbara, G.; Avoni, P.; Liguori, R.; Petrolini, N.; Fiorini, E.; Montagna, P. Anti-ganglioside antibodies in coeliac disease with neurological disorders. Dig. Liver Dis. 2006, 38, 183–187.
  83. Kayali, S.; Selbuz, S. Assessment of Autonomic Nervous System in Children with Celiac Disease: A Heart Rate Variability Study. Indian Pediatr. 2020, 57, 719–722.
  84. Przybylska-Felus, M.; Furgala, A.; Zwolinska-Wcislo, M.; Mazur, M.; Widera, A.; Thor, P.; Mach, T. Disturbances of autonomic nervous system activity and diminished response to stress in patients with celiac disease. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 2014, 65.
  85. Guy-Grand, D.; DiSanto, J.P.; Henchoz, P.; Malassis-Séris, M.; Vassalli, P. Small bowel enteropathy: Role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-gamma, TNF) in the induction of epithelial cell death and renewal. Eur. J. Immunol. 1998, 28, 730–744.
  86. Sekirov, I.; Russell, S.L.; Antunes, L.C.M.; Finlay, B.B. Gut Microbiota in Health and Disease. Physiol. Rev. 2010, 90, 859–904.
  87. Sprockett, D.; Fukami, T.; Relman, D.A. Role of priority effects in the early-life assembly of the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 197–205.
  88. Palmer, C.; Bik, E.M.; DiGiulio, D.B.; Relman, D.A.; Brown, P.O. Development of the Human Infant Intestinal Microbiota. PLoS Biol. 2007, 5, e177.
  89. Umesaki, Y.; Setoyama, H.; Matsumoto, S.; Okada, Y. Expansion of alpha beta T-cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology 1993, 79, 32–37.
  90. Macfarlane, S.; Macfarlane, G.T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 2003, 62, 67–72.
  91. Bellocchi, C.; Volkmann, E.R. Update on the Gastrointestinal Microbiome in Systemic Sclerosis. Curr. Rheumatol. Rep. 2018, 20, 49.
  92. Seksik, P.; Rigottier-Gois, L.; Gramet, G.; Sutren, M.; Pochart, P.; Marteau, P.; Jian, R.; Doré, J. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut 2003, 52, 237–242.
  93. Pozuelo, M.; Panda, S.; Santiago, A.; Mendez, S.; Accarino, A.; Santos, J.; Guarner, F.; Azpiroz, F.; Manichanh, C. Reduction of butyrate- and methane-producing microorganisms in patients with Irritable Bowel Syndrome. Sci. Rep. 2015, 5, 12693.
  94. Bellocchi, C.; Fernández-Ochoa, Á.; Montanelli, G.; Vigone, B.; Santaniello, A.; Milani, C.; Quirantes-Piné, R.; Borrás-Linares, I.; Ventura, M.; Segura-Carrettero, A.; et al. Microbial and metabolic multi-omic correlations in systemic sclerosis patients. Ann. N. Y. Acad. Sci. 2018, 1421, 97–109.
  95. Chen, B.; Jia, X.; Xu, J.; Zhao, L.; Ji, J.; Wu, B.; Ma, Y.; Li, H.; Zuo, X.; Pan, W.; et al. An Autoimmunogenic and Proinflammatory Profile Defined by the Gut Microbiota of Patients With Untreated Systemic Lupus Erythematosus. Arthritis Rheumatol. 2020, 73, 232–243.
  96. Tait, C.; Sayuk, G.S. The Brain-Gut-Microbiotal Axis: A framework for understanding functional GI illness and their therapeutic interventions. Eur. J. Intern. Med. 2021, 84, 1–9.
  97. Mayer, E.A. Gut feelings: The emerging biology of gut–brain communication. Nat. Rev. Neurosci. 2011, 12, 453–466.
  98. Mayer, E.A.; Knight, R.; Mazmanian, S.K.; Cryan, J.F.; Tillisch, K. Gut Microbes and the Brain: Paradigm Shift in Neuroscience. J. Neurosci. 2014, 34, 15490–15496.
  99. Martin, C.R.; Osadchiy, V.; Kalani, A.; Mayer, E.A. The Brain-Gut-Microbiome Axis. Cell. Mol. Gastroenterol. Hepatol. 2018, 6, 133–148.
  100. Mayer, E.A.; Tillisch, K. The Brain-Gut Axis in Abdominal Pain Syndromes. Annu. Rev. Med. 2011, 62, 381–396.
  101. Berman, S.M.; Naliboff, B.D.; Suyenobu, B.; Labus, J.S.; Stains, J.; Ohning, G.; Kilpatrick, L.; Bueller, J.A.; Ruby, K.; Jarcho, J.; et al. Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome. J. Neurosci. 2008, 28, 349–359.
  102. Neufeld, K.M.; Kang, N.; Bienenstock, J.; Foster, J.A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 2010, 23, 255-e119.
  103. Kelly, J.; Borre, Y.; Brien, C.O.; Patterson, E.; El Aidy, S.; Deane, J.; Kennedy, P.J.; Beers, S.; Scott, K.; Moloney, G.; et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 2016, 82, 109–118.
  104. Bonaz, B.; Sinniger, V.; Pellissier, S. The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract. Front. Immunol. 2017, 8, 1452.
  105. Furness, J.B. Integrated Neural and Endocrine Control of Gastrointestinal Function. Enteric Nerv. Syst. 2016, 891, 159–173.
  106. Diepenbroek, C.; Quinn, D.; Stephens, R.; Zollinger, B.; Anderson, S.; Pan, A.; De Lartigue, G. Validation and characterization of a novel method for selective vagal deafferentation of the gut. Am. J. Physiol. Liver Physiol. 2017, 313, G342–G352.
  107. Powell, N.; Walker, M.M.; Talley, N.J. The mucosal immune system: Master regulator of bidirectional gut–brain communications. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 143–159.
  108. Bartley, A.; Yang, T.; Arocha, R.; Malphurs, W.L.; Larkin, R.; Magee, K.L.; Vickroy, T.W.; Zubcevic, J. Increased Abundance of Lactobacillales in the Colon of Beta-Adrenergic Receptor Knock Out Mouse Is Associated With Increased Gut Bacterial Production of Short Chain Fatty Acids and Reduced IL17 Expression in Circulating CD4+ Immune Cells. Front. Physiol. 2018, 9.
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