The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Paul WE. 1.  1983. Preface. Annu. Rev. Immunol. 1:1 [Google Scholar]
  2. Tracey KJ. 2.  2010. Understanding immunity requires more than immunology. Nat. Immunol. 11:561–64 [Google Scholar]
  3. Talbot S, Foster SL, Woolf CJ. 3.  2016. Neuroimmunity: physiology and pathology. Annu. Rev. Immunol. 34:421–47 [Google Scholar]
  4. Bonaz B, Sinniger V, Hoffmann D, Clarencon D, Mathieu N. 4.  et al. 2016. Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study. Neurogastroenterol. Motil. 28:948–53 [Google Scholar]
  5. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S. 5.  et al. 2016. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. PNAS 113:8284–89 [Google Scholar]
  6. Yoo BB, Mazmanian SK. 6.  2017. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46:910–26 [Google Scholar]
  7. Ransohoff RM, Perry VH. 7.  2009. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27:119–45 [Google Scholar]
  8. Sofroniew MV. 8.  2015. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16:249–63 [Google Scholar]
  9. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. 9.  2010. Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–34 [Google Scholar]
  10. Webster JI, Tonelli L, Sternberg EM. 10.  2002. Neuroendocrine regulation of immunity. Annu. Rev. Immunol. 20:125–63 [Google Scholar]
  11. Chrousos GP. 11.  1995. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332:1351–62 [Google Scholar]
  12. Slominski AT, Zmijewski MA, Zbytek B, Tobin DJ, Theoharides TC, Rivier J. 12.  2013. Key role of CRF in the skin stress response system. Endocr. Rev. 34:827–84 [Google Scholar]
  13. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. 13.  2000. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52:595–638 [Google Scholar]
  14. Jänig W. 14.  2014. Sympathetic nervous system and inflammation: a conceptual view. Auton. Neurosci. 182:4–14 [Google Scholar]
  15. Jänig W, Keast JR, McLachlan EM, Neuhuber WL, Southard-Smith M. 15.  2017. Renaming all spinal autonomic outflows as sympathetic is a mistake. Auton. Neurosci. 206:60–62 [Google Scholar]
  16. Goyal RK, Hirano I. 16.  1996. The enteric nervous system. N. Engl. J. Med. 334:1106–15 [Google Scholar]
  17. Dubin AE, Patapoutian A. 17.  2010. Nociceptors: the sensors of the pain pathway. J. Clin. Investig. 120:3760–72 [Google Scholar]
  18. Chavan SS, Pavlov VA, Tracey KJ. 18.  2017. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46:927–42 [Google Scholar]
  19. Mazzone SB, Undem BJ. 19.  2016. Vagal afferent innervation of the airways in health and disease. Physiol. Rev. 96:975–1024 [Google Scholar]
  20. Berthoud HR, Neuhuber WL. 20.  2000. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85:1–17 [Google Scholar]
  21. Pavlov VA, Tracey KJ. 21.  2012. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat. Rev. Endocrinol. 8:743–54 [Google Scholar]
  22. Yaprak M. 22.  2008. The axon reflex. Neuroanatomy 7:17–19 [Google Scholar]
  23. Barnes PJ. 23.  1986. Asthma as an axon reflex. Lancet 1:242–45 [Google Scholar]
  24. Nieuwenhoff MD, Wu Y, Huygen FJ, Schouten AC, van der Helm FC, Niehof SP. 24.  2016. Reproducibility of axon reflex-related vasodilation assessed by dynamic thermal imaging in healthy subjects. Microvasc. Res. 106:1–7 [Google Scholar]
  25. Houghton BL, Meendering JR, Wong BJ, Minson CT. 25.  2006. Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin. J. Physiol. 572:811–20 [Google Scholar]
  26. Abboud FM, Thames MD. 26.  2011 (1983). Interaction of cardiovascular reflexes in circulatory control. Comprehensive Physiology, Suppl. 8: Handbook of Physiology; The Cardiovascular System, Peripheral Circulation and Organ Blood Flow675–753 New York: Wiley [Google Scholar]
  27. Dampney RA. 27.  2016. Central neural control of the cardiovascular system: current perspectives. Adv. Physiol. Educ. 40:283–96 [Google Scholar]
  28. Mayer EA. 28.  2011. Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 12:453–66 [Google Scholar]
  29. Travagli RA, Hermann GE, Browning KN, Rogers RC. 29.  2006. Brainstem circuits regulating gastric function. Annu. Rev. Physiol. 68:279–305 [Google Scholar]
  30. Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S. 30.  et al. 2013. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J. Neurosci. 33:12970–81 [Google Scholar]
  31. Ueno M, Ueno-Nakamura Y, Niehaus J, Popovich PG, Yoshida Y. 31.  2016. Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury. Nat. Neurosci. 19:784–87 [Google Scholar]
  32. Jerne NK. 32.  1974. Towards a network theory of the immune system. Ann. Immunol. 125C:373–89 [Google Scholar]
  33. Hosoi T, Okuma Y, Matsuda T, Nomura Y. 33.  2005. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton. Neurosci. 120:104–7 [Google Scholar]
  34. de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. 34.  2011. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am. J. Physiol. Endocrinol. Metab. 301:E187–95 [Google Scholar]
  35. Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T. 35.  et al. 2015. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat. Med 21:1326–31 [Google Scholar]
  36. Park CK, Xu ZZ, Berta T, Han Q, Chen G. 36.  et al. 2014. Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82:47–54 [Google Scholar]
  37. Steinberg BE, Silverman HA, Robbiati S, Gunasekaran MK, Tsaava T. 37.  et al. 2016. Cytokine-specific neurograms in the sensory vagus nerve. Bioelectron. Med. 3:7–17 [Google Scholar]
  38. Kawashima K, Fujii T, Moriwaki Y, Misawa H. 38.  2012. Critical roles of acetylcholine and the muscarinic and nicotinic acetylcholine receptors in the regulation of immune function. Life Sci 91:1027–32 [Google Scholar]
  39. Kawashima K, Fujii T, Moriwaki Y, Misawa H, Horiguchi K. 39.  2015. Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs. Int. Immunopharmacol. 29:127–34 [Google Scholar]
  40. Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA. 40.  et al. 2011. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334:98–101 [Google Scholar]
  41. Marino F, Cosentino M. 41.  2013. Adrenergic modulation of immune cells: an update. Amino. Acids 45:55–71 [Google Scholar]
  42. Chiu IM, Heesters BA, Ghasemlou N, von Hehn CA, Zhao F. 42.  et al. 2013. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501:52–57 [Google Scholar]
  43. Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. 43.  2003. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol. Med. 9:125–34 [Google Scholar]
  44. Capuron L, Miller AH. 44.  2011. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol. Ther. 130:226–38 [Google Scholar]
  45. Pinho-Ribeiro FA, Verri WA Jr, Chiu IM. 45.  2017. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol 38:5–19 [Google Scholar]
  46. Lai NY, Mills K, Chiu IM. 46.  2017. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J. Intern. Med. 282:5–23 [Google Scholar]
  47. Julius D. 47.  2013. TRP channels and pain. Annu. Rev. Cell Dev. Biol. 29:355–84 [Google Scholar]
  48. Schaible HG. 48.  2014. Nociceptive neurons detect cytokines in arthritis. Arthritis Res. Ther. 16:470 [Google Scholar]
  49. Nicol GD, Lopshire JC, Pafford CM. 49.  1997. Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons. J. Neurosci. 17:975–82 [Google Scholar]
  50. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D. 50.  et al. 2008. Nociceptors are interleukin-1β sensors. J. Neurosci. 28:14062–73 [Google Scholar]
  51. Nassenstein C, Kwong K, Taylor-Clark T, Kollarik M, Macglashan DM. 51.  et al. 2008. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J. Physiol. 586:1595–604 [Google Scholar]
  52. Kollarik M, Ru F, Brozmanova M. 52.  2010. Vagal afferent nerves with the properties of nociceptors. Auton. Neurosci. 153:12–20 [Google Scholar]
  53. Browning KN, Verheijden S, Boeckxstaens GE. 53.  2017. The vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology 152:730–44 [Google Scholar]
  54. Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M. 54.  2005. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. . Brain Behav. Immun. 19:334–44 [Google Scholar]
  55. Ek M, Kurosawa M, Lundeberg T, Ericsson A. 55.  1998. Activation of vagal afferents after intravenous injection of interleukin-1β: role of endogenous prostaglandins. J. Neurosci. 18:9471–79 [Google Scholar]
  56. Marvel FA, Chen CC, Badr N, Gaykema RP, Goehler LE. 56.  2004. Reversible inactivation of the dorsal vagal complex blocks lipopolysaccharide-induced social withdrawal and c-Fos expression in central autonomic nuclei. Brain Behav. Immun. 18:123–34 [Google Scholar]
  57. Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR. 57.  2000. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton. Neurosci. 85:49–59 [Google Scholar]
  58. Niijima A. 58.  1996. The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat. J. Auton. Nerv. Syst. 61:287–91 [Google Scholar]
  59. Goehler LE, Gaykema RP, Hammack SE, Maier SF, Watkins LR. 59.  1998. Interleukin-1 induces c-Fos immunoreactivity in primary afferent neurons of the vagus nerve. Brain Res 804:306–10 [Google Scholar]
  60. Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ. 60.  et al. 2015. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87:341–54 [Google Scholar]
  61. Feng J, Yang P, Mack MR, Dryn D, Luo J. 61.  et al. 2017. Sensory TRP channels contribute differentially to skin inflammation and persistent itch. Nat. Commun. 8:980 [Google Scholar]
  62. Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H. 62.  et al. 2017. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171:217–28 [Google Scholar]
  63. Chiu IM, von Hehn CA, Woolf CJ. 63.  2012. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15:1063–67 [Google Scholar]
  64. Klose CSN, Mahlakoiv T, Moeller JB, Rankin LC, Flamar AL. 64.  et al. 2017. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549:282–86 [Google Scholar]
  65. Wallrapp A, Riesenfeld SJ, Burkett PR, Abdulnour RE, Nyman J. 65.  et al. 2017. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351–56 [Google Scholar]
  66. Cardoso V, Chesne J, Ribeiro H, Garcia-Cassani B, Carvalho T. 66.  et al. 2017. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549:277–81 [Google Scholar]
  67. Hanes WM, Olofsson PS, Talbot S, Tsaava T, Ochani M. 67.  et al. 2016. Neuronal circuits modulate antigen flow through lymph nodes. Bioelectron. Med. 3:18–29 [Google Scholar]
  68. Nathan C, Ding A. 68.  2010. Nonresolving inflammation. Cell 140:871–82 [Google Scholar]
  69. Andersson U, Tracey KJ. 69.  2012. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30:313–35 [Google Scholar]
  70. Sternberg EM. 70.  2006. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 6:318–28 [Google Scholar]
  71. Besser MJ, Ganor Y, Levite M. 71.  2005. Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFα or both. J. Neuroimmunol. 169:161–71 [Google Scholar]
  72. Scheiermann C, Kunisaki Y, Lucas D, Chow A, Jang JE. 72.  et al. 2012. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37:290–301 [Google Scholar]
  73. Williams JM, Peterson RG, Shea PA, Schmedtje JF, Bauer DC, Felten DL. 73.  1981. Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune systems. Brain Res. Bull. 6:83–94 [Google Scholar]
  74. Miksa M, Das P, Zhou M, Wu R, Dong W. 74.  et al. 2009. Pivotal role of the α2A-adrenoceptor in producing inflammation and organ injury in a rat model of sepsis. PLOS ONE 4:e5504 [Google Scholar]
  75. Grisanti LA, Woster AP, Dahlman J, Sauter ER, Combs CK, Porter JE. 75.  2011. α1-Adrenergic receptors positively regulate Toll-like receptor cytokine production from human monocytes and macrophages. J. Pharmacol. Exp. Ther. 338:648–57 [Google Scholar]
  76. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ. 76.  et al. 2006. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124:407–21 [Google Scholar]
  77. Nakai A, Hayano Y, Furuta F, Noda M, Suzuki K. 77.  2014. Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. J. Exp. Med. 211:2583–98 [Google Scholar]
  78. Tracey KJ. 78.  2014. Lymphocyte called home: β2-adreneric neurotransmission confines T cells to lymph nodes to suppress inflammation. J. Exp. Med. 211:2483–84 [Google Scholar]
  79. Gabanyi I, Muller PA, Feighery L, Oliveira TY, Costa-Pinto FA, Mucida D. 79.  2016. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164:378–91 [Google Scholar]
  80. Medzhitov R, Schneider DS, Soares MP. 80.  2012. Disease tolerance as a defense strategy. Science 335:936–41 [Google Scholar]
  81. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P. 81.  2011. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334:101–5 [Google Scholar]
  82. McCulloch L, Smith CJ, McColl BW. 82.  2017. Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke. Nat. Commun. 8:15051 [Google Scholar]
  83. Langhorne P, Stott DJ, Robertson L, MacDonald J, Jones L. 83.  et al. 2000. Medical complications after stroke: a multicenter study. Stroke 31:1223–29 [Google Scholar]
  84. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. 84.  2005. Central nervous system injury-induced immune deficiency syndrome. Nat. Rev. Neurosci. 6:775–86 [Google Scholar]
  85. Prass K, Meisel C, Hoflich C, Braun J, Halle E. 85.  et al. 2003. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J. Exp. Med. 198:725–36 [Google Scholar]
  86. Oke SL, Tracey KJ. 86.  2008. From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex. J. Leukoc. Biol. 83:512–17 [Google Scholar]
  87. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI. 87.  et al. 2000. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–62 [Google Scholar]
  88. Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K. 88.  et al. 2006. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 203:1623–28 [Google Scholar]
  89. Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM. 89.  et al. 2006. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. PNAS 103:5219–23 [Google Scholar]
  90. Olofsson PS, Levine YA, Caravaca A, Chavan SS, Pavlov VA. 90.  et al. 2015. Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces tumor necrosis factor in endotoxemia. Bioelectron. Med. 2:37–42 [Google Scholar]
  91. Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R. 91.  et al. 2007. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit. Care Med. 35:2762–68 [Google Scholar]
  92. Levine YA, Koopman FA, Faltys M, Caravaca A, Bendele A. 92.  et al. 2014. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLOS ONE 9:e104530 [Google Scholar]
  93. Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C. 93.  et al. 2011. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton. Neurosci. 160:82–89 [Google Scholar]
  94. Ghia JE, Blennerhassett P, El Sharkawy RT, Collins SM. 94.  2007. The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 293:G711–18 [Google Scholar]
  95. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. 95.  2006. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131:1122–30 [Google Scholar]
  96. Guarini S, Cainazzo MM, Giuliani D, Mioni C, Altavilla D. 96.  et al. 2004. Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway. Cardiovasc. Res. 63:357–65 [Google Scholar]
  97. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ. 97.  et al. 2005. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6:844–51 [Google Scholar]
  98. Inoue T, Abe C, Sung SS, Moscalu S, Jankowski J. 98.  et al. 2016. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J. Clin. Investig. 126:1939–52 [Google Scholar]
  99. Pavlov VA. 99.  2008. Cholinergic modulation of inflammation. Int. J. Clin. Exp. Med. 1:203–12 [Google Scholar]
  100. Tracey KJ. 100.  2007. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Investig. 117:289–96 [Google Scholar]
  101. Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D. 101.  et al. 2005. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J. Exp. Med. 201:1113–23 [Google Scholar]
  102. Huston JM, Rosas-Ballina M, Xue X, Dowling O, Ochani K. 102.  et al. 2009. Cholinergic neural signals to the spleen down-regulate leukocyte trafficking via CD11b. J. Immunol. 183:552–59 [Google Scholar]
  103. Wang H, Yu M, Ochani M, Amella CA, Tanovic M. 103.  et al. 2003. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421:384–88 [Google Scholar]
  104. Olofsson PS, Katz DA, Rosas-Ballina M, Levine YA, Ochani M. 104.  et al. 2012. α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol. Med. 18:539–43 [Google Scholar]
  105. Guarini S, Altavilla D, Cainazzo MM, Giuliani D, Bigiani A. 105.  et al. 2003. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107:1189–94 [Google Scholar]
  106. Lu B, Kwan K, Levine YA, Olofsson PS, Yang H. 106.  et al. 2014. α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Mol. Med. 20:350–58 [Google Scholar]
  107. Serhan CN. 107.  2014. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510:92–101 [Google Scholar]
  108. Serhan CN, Chiang N, Dalli J. 108.  2015. The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin. Immunol. 27:200–15 [Google Scholar]
  109. Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN. 109.  2014. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J. Exp. Med. 211:1037–48 [Google Scholar]
  110. Dalli J, Colas RA, Arnardottir H, Serhan CN. 110.  2017. Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity 46:92–105 [Google Scholar]
  111. Tracey KJ. 111.  2002. The inflammatory reflex. Nature 420:853–59 [Google Scholar]
  112. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT. 112.  et al. 2008. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. PNAS 105:11008–13 [Google Scholar]
  113. Pavlov VA, Tracey KJ. 113.  2015. Neural circuitry and immunity. Immunol. Res. 63:38–57 [Google Scholar]
  114. Berthoud HR, Powley TL. 114.  1993. Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia. J. Auton. Nerv. Syst. 42:153–69 [Google Scholar]
  115. Berthoud HR, Powley TL. 115.  1996. Interaction between parasympathetic and sympathetic nerves in prevertebral ganglia: morphological evidence for vagal efferent innervation of ganglion cells in the rat. Microsc. Res. Tech. 35:80–86 [Google Scholar]
  116. Bellinger DL, Felten SY, Lorton D, Felten DL. 116.  1989. Origin of noradrenergic innervation of the spleen in rats. Brain Behav. Immun. 3:291–311 [Google Scholar]
  117. Li M, Galligan J, Wang D, Fink G. 117.  2010. The effects of celiac ganglionectomy on sympathetic innervation to the splanchnic organs in the rat. Auton. Neurosci. 154:66–73 [Google Scholar]
  118. Nance DM, Burns J. 118.  1989. Innervation of the spleen in the rat: evidence for absence of afferent innervation. Brain Behav. Immun. 3:281–90 [Google Scholar]
  119. Straub RH. 119.  2004. Complexity of the bi-directional neuroimmune junction in the spleen. Trends Pharmacol. Sci. 25:640–46 [Google Scholar]
  120. Pavlov VA, Tracey KJ. 120.  2017. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat. Neurosci. 20:156–66 [Google Scholar]
  121. Mina-Osorio P, Rosas-Ballina M, Valdes-Ferrer SI, Al Abed Y, Tracey KJ, Diamond B. 121.  2012. Neural signaling in the spleen controls B-cell responses to blood-borne antigen. Mol. Med. 18:618–27 [Google Scholar]
  122. Carnevale D, Perrotta M, Pallante F, Fardella V, Iacobucci R. 122.  et al. 2016. A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication. Nat. Commun. 7:13035 [Google Scholar]
  123. Chavan SS, Tracey KJ. 123.  2017. Essential neuroscience in immunology. J. Immunol. 198:3389–97 [Google Scholar]
  124. Song JG, Li HH, Cao YF, Lv X, Zhang P. 124.  et al. 2012. Electroacupuncture improves survival in rats with lethal endotoxemia via the autonomic nervous system. Anesthesiology 116:406–14 [Google Scholar]
  125. Torres-Rosas R, Yehia G, Pena G, Mishra P, Rocio Thompson-Bonilla M. 125.  et al. 2014. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat. Med. 20:291–95 [Google Scholar]
  126. Arima Y, Harada M, Kamimura D, Park JH, Kawano F. 126.  et al. 2012. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148:447–57 [Google Scholar]
  127. Sabharwal L, Kamimura D, Meng J, Bando H, Ogura H. 127.  et al. 2014. The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS. J Biochem 156:299–304 [Google Scholar]
  128. Brommer B, Engel O, Kopp MA, Watzlawick R, Muller S. 128.  et al. 2016. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain 139:692–707 [Google Scholar]
  129. Ossipov MH, Dussor GO, Porreca F. 129.  2010. Central modulation of pain. J. Clin. Investig. 120:3779–87 [Google Scholar]
  130. Lumpkin EA, Caterina MJ. 130.  2007. Mechanisms of sensory transduction in the skin. Nature 445:858–65 [Google Scholar]
  131. Heinricher MM, Tavares I, Leith JL, Lumb BM. 131.  2009. Descending control of nociception: specificity, recruitment and plasticity. Brain Res. Rev. 60:214–25 [Google Scholar]
  132. Berthoud HR. 132.  2004. Anatomy and function of sensory hepatic nerves. Anat. Rec. A 280:827–35 [Google Scholar]
  133. Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD. 133.  2015. Vagal sensory neuron subtypes that differentially control breathing. Cell 161:622–33 [Google Scholar]
  134. Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD. 134.  2016. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166:209–21 [Google Scholar]
  135. Bouton C. 135.  2017. Cracking the neural code, treating paralysis and the future of bioelectronic medicine. J. Intern. Med. 282:37–45 [Google Scholar]
  136. Monnikes H, Lauer G, Arnold R. 136.  1997. Peripheral administration of cholecystokinin activates c-fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rat. Brain Res 770:277–88 [Google Scholar]
  137. Turnbull AV, Rivier CL. 137.  1999. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol. Rev. 79:1–71 [Google Scholar]
  138. Shipley MT. 138.  1982. Insular cortex projection to the nucleus of the solitary tract and brainstem visceromotor regions in the mouse. Brain Res. Bull. 8:139–48 [Google Scholar]
  139. Benarroch EE. 139.  1993. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin. Proc. 68:988–1001 [Google Scholar]
  140. Wrona D. 140.  2006. Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J. Neuroimmunol. 172:38–58 [Google Scholar]
  141. Haas HS, Schauenstein K. 141.  1997. Neuroimmunomodulation via limbic structures—the neuroanatomy of psychoimmunology. Prog. Neurobiol. 51:195–222 [Google Scholar]
  142. Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M. 142.  et al. 2009. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav. Immun. 23:41–45 [Google Scholar]
  143. Ji H, Rabbi MF, Labis B, Pavlov VA, Tracey KJ, Ghia JE. 143.  2014. Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol 7:335–47 [Google Scholar]
  144. Rosas-Ballina M, Valdes-Ferrer SI, Dancho ME, Ochani M, Katz D. 144.  et al. 2015. Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. Brain Behav. Immun. 44:19–27 [Google Scholar]
  145. Ben Shaanan TL, Azulay-Debby H, Dubovik T, Starosvetsky E, Korin B. 145.  et al. 2016. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22:940–44 [Google Scholar]
  146. Pavlov VA, Lehner KR, Silverman HA, Tsaava T, Chavan SS, Tracey KJ. 146.  2016. Optogenetic stimulation of brain cholinergic networks suppresses inflammation. J. Immunol. 196:1 Suppl.69.24 [Google Scholar]
  147. Abe C, Inoue T, Inglis MA, Viar KE, Huang L. 147.  et al. 2017. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20:700–7 [Google Scholar]
  148. Ballinger EC, Ananth M, Talmage DA, Role LW. 148.  2016. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 91:1199–218 [Google Scholar]
  149. Girault JA, Greengard P. 149.  2004. The neurobiology of dopamine signaling. Arch. Neurol. 61:641–44 [Google Scholar]
  150. Zador AM, Dubnau J, Oyibo HK, Zhan H, Cao G, Peikon ID. 150.  2012. Sequencing the connectome. PLOS Biol 10:e1001411 [Google Scholar]
  151. Gore BB, Soden ME, Zweifel LS. 151.  2013. Manipulating gene expression in projection-specific neuronal populations using combinatorial viral approaches. Curr. Protoc. Neurosci. 65:4–20 [Google Scholar]
  152. Oh SW, Harris JA, Ng L, Winslow B, Cain N. 152.  et al. 2014. A mesoscale connectome of the mouse brain. Nature 508:207–14 [Google Scholar]
  153. Cabrera LY, Evans EL, Hamilton RH. 153.  2014. Ethics of the electrified mind: defining issues and perspectives on the principled use of brain stimulation in medical research and clinical care. Brain Topogr 27:33–45 [Google Scholar]
  154. Hyam JA, Kringelbach ML, Silburn PA, Aziz TZ, Green AL. 154.  2012. The autonomic effects of deep brain stimulation—a therapeutic opportunity. Nat. Rev. Neurol. 8:391–400 [Google Scholar]
  155. Bouton CE, Shaikhouni A, Annetta NV, Bockbrader MA, Friedenberg DA. 155.  et al. 2016. Restoring cortical control of functional movement in a human with quadriplegia. Nature 533:247–50 [Google Scholar]
  156. Tracey KJ. 156.  2015. Shock medicine. Sci. Am. 312:28–35 [Google Scholar]
  157. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F. 157.  et al. 2015. Neuroinflammation in Alzheimer's disease. Lancet Neurol 14:388–405 [Google Scholar]
  158. Kirkpatrick B, Miller BJ. 158.  2013. Inflammation and schizophrenia. Schizophr. Bull. 39:1174–79 [Google Scholar]
  159. Meyer U, Schwarz MJ, Muller N. 159.  2011. Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacol. Ther. 132:96–110 [Google Scholar]
  160. Silverman HA, Dancho M, Regnier-Golanov A, Nasim M, Ochani M. 160.  et al. 2014. Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin-induced inflammation. Mol. Med. 20:601–11 [Google Scholar]
  161. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. 161.  2015. Systemic inflammation and microglial activation: systematic review of animal experiments. J. Neuroinflammation 12:114 [Google Scholar]
  162. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D. 162.  et al. 2016. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801–10 [Google Scholar]
  163. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC. 163.  et al. 2015. Sepsis: a roadmap for future research. Lancet Infect. Dis. 15:581–614 [Google Scholar]
  164. Delano MJ, Ward PA. 164.  2016. Sepsis-induced immune dysfunction: can immune therapies reduce mortality?. J. Clin. Investig. 126:23–31 [Google Scholar]
  165. Mira JC, Gentile LF, Mathias BJ, Efron PA, Brakenridge SC. 165.  et al. 2017. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit. Care Med. 45:253–62 [Google Scholar]
  166. Gofton TE, Young GB. 166.  2012. Sepsis-associated encephalopathy. Nat. Rev. Neurol. 8:557–66 [Google Scholar]
  167. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL. 167.  et al. 2010. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit. Care Med. 38:1513–20 [Google Scholar]
  168. van Gool WA, van de Beek D, Eikelenboom P. 168.  2010. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375:773–75 [Google Scholar]
  169. Lemstra AW, Groen in't Woud JC, Hoozemans JJ, van Haastert ES, Rozemuller AJ. 169.  et al. 2007. Microglia activation in sepsis: a case-control study. J. Neuroinflammation 4:4 [Google Scholar]
  170. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. 170.  2008. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J. Gerontol. A 63:764–72 [Google Scholar]
  171. Trzepacz PT. 171.  2000. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin. Clin. Neuropsychiatry 5:132–48 [Google Scholar]
  172. Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T. 172.  et al. 2007. Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp. Neurol. 204:733–40 [Google Scholar]
  173. Deutschman CS, Raj NR, McGuire EO, Kelz MB. 173.  2013. Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis. Crit. Care Med. 41:e368–75 [Google Scholar]
  174. Iwashyna TJ, Ely EW, Smith DM, Langa KM. 174.  2010. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304:1787–94 [Google Scholar]
  175. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE. 175.  2010. Long-term mortality and quality of life in sepsis: a systematic review. Crit. Care Med. 38:1276–83 [Google Scholar]
  176. Valdes-Ferrer SI, Rosas-Ballina M, Olofsson PS, Lu B, Dancho ME. 176.  et al. 2013. HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-6Chigh inflammatory monocytes in murine sepsis survivors. J. Intern. Med. 274:381–90 [Google Scholar]
  177. Chavan SS, Huerta PT, Robbiati S, Valdes-Ferrer SI, Ochani M. 177.  et al. 2012. HMGB1 mediates cognitive impairment in sepsis survivors. Mol. Med. 18:930–37 [Google Scholar]
  178. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. 178.  2010. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. PNAS 107:20518–22 [Google Scholar]
  179. Felipo V. 179.  2013. Hepatic encephalopathy: effects of liver failure on brain function. Nat. Rev. Neurosci. 14:851–58 [Google Scholar]
  180. Coltart I, Tranah TH, Shawcross DL. 180.  2013. Inflammation and hepatic encephalopathy. Arch. Biochem. Biophys. 536:189–96 [Google Scholar]
  181. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS. 181.  2009. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110:548–55 [Google Scholar]
  182. Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C. 182.  et al. 2010. Role of interleukin-1β in postoperative cognitive dysfunction. Ann. Neurol. 68:360–68 [Google Scholar]
  183. Garcia-Ayllon MS, Cauli O, Silveyra MX, Rodrigo R, Candela A. 183.  et al. 2008. Brain cholinergic impairment in liver failure. Brain 131:2946–56 [Google Scholar]
  184. Barron HV, Alam I, Lesh MD, Strunk A, Bass NM. 184.  1999. Autonomic nervous system tone measured by baroreflex sensitivity is depressed in patients with end-stage liver disease. Am. J. Gastroenterol. 94:986–89 [Google Scholar]
  185. Mani AR, Montagnese S, Jackson CD, Jenkins CW, Head IM. 185.  et al. 2009. Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 296:G330–38 [Google Scholar]
  186. Mackay M. 186.  2015. Lupus brain fog: a biologic perspective on cognitive impairment, depression, and fatigue in systemic lupus erythematosus. Immunol. Res. 63:26–37 [Google Scholar]
  187. Brimberg L, Mader S, Fujieda Y, Arinuma Y, Kowal C. 187.  et al. 2015. Antibodies as mediators of brain pathology. Trends Immunol 36:709–24 [Google Scholar]
  188. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. 188.  2009. Losing your nerves? Maybe it's the antibodies. Nat. Rev. Immunol. 9:449–56 [Google Scholar]
  189. Diamond B, Volpe BT. 189.  2012. A model for lupus brain disease. Immunol. Rev. 248:56–67 [Google Scholar]
  190. Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. 190.  2013. Brain-reactive antibodies and disease. Annu. Rev. Immunol. 31:345–85 [Google Scholar]
  191. Chang EH, Volpe BT, Mackay M, Aranow C, Watson P. 191.  et al. 2015. Selective impairment of spatial cognition caused by autoantibodies to the N-methyl-d-aspartate receptor. EBioMedicine 2:755–64 [Google Scholar]
  192. Bloom O, Cheng KF, He M, Papatheodorou A, Volpe BT. 192.  et al. 2011. Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. PNAS 108:10255–59 [Google Scholar]
  193. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC. 193.  et al. 2000. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. PNAS 97:10526–31 [Google Scholar]
  194. Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K. 194.  et al. 2007. Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit. Care Med. 35:1139–44 [Google Scholar]
  195. Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K. 195.  et al. 2008. Modulation of TNF release by choline requires α7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol. Med. 14:567–74 [Google Scholar]
  196. Norman GJ, Morris JS, Karelina K, Weil ZM, Zhang N. 196.  et al. 2011. Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic α7 nicotinic receptors. J. Neurosci. 31:3446–52 [Google Scholar]
  197. Terrando N, Yang T, Ryu JK, Newton PT, Monaco C. 197.  et al. 2014. Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Mol. Med. 20:667–75 [Google Scholar]
  198. Hoover DB. 198.  2017. Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol. Ther. 179:1–16 [Google Scholar]
  199. Gowayed MA, Refaat R, Ahmed WM, El Abhar HS. 199.  2015. Effect of galantamine on adjuvant-induced arthritis in rats. Eur. J. Pharmacol. 764:547–53 [Google Scholar]
  200. Satapathy SK, Ochani M, Dancho M, Hudson LK, Rosas-Ballina M. 200.  et al. 2011. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet–fed mice. Mol. Med. 17:599–606 [Google Scholar]
  201. Grundy SM. 201.  2008. Metabolic syndrome pandemic. Arterioscler. Thromb. Vasc. Biol. 28:629–36 [Google Scholar]
  202. Consolim-Colombo F, Sangaleti CT, Costa FO, Morais TL, Lopes HF. 202.  et al. 2017. Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. JCI Insight https://doi.org/10.1172/jci.insight.93340 [Crossref]
  203. Hunter TM, Boytsov NN, Zhang X, Schroeder K, Michaud K, Araujo AB. 203.  2017. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004-2014. Rheumatol. Int. 37:1551–57 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error