Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Somatosensory and autonomic neuronal regulation of the immune response

Nature Reviews Neuroscience volume 23, pages 157–171 (2022)Cite this article

Subjects

Abstract

Bidirectional communication between the peripheral nervous system (PNS) and the immune system is a crucial part of an effective but balanced mammalian response to invading pathogens, tissue damage and inflammatory stimuli. Here, we review how somatosensory and autonomic neurons regulate immune cellular responses at barrier tissues and in peripheral organs. Immune cells express receptors for neuronal mediators, including neuropeptides and neurotransmitters, allowing neurons to influence their function in acute and chronic inflammatory diseases. Distinct subsets of peripheral sensory, sympathetic, parasympathetic and enteric neurons are able to signal to innate and adaptive immune cells to modulate their cellular functions. In this Review, we highlight recent studies defining the molecular mechanisms by which neuroimmune signalling mediates tissue homeostasis and pathology. Understanding the neural circuitry that regulates immune responses can offer novel targets for the treatment of a wide array of diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Examples of sensory neuron–immune cell interactions in the skin.
Fig. 2: Examples of sensory neuron–immune cell interactions in the respiratory tract.
Fig. 3: Examples of sympathetic neuron–immune cell interactions.
Fig. 4: Examples of parasympathetic regulation of immune cells.
Fig. 5: Examples of enteric neuron–immune cell interactions.

Similar content being viewed by others

References

  1. Veiga-Fernandes, H. & Pachnis, V. Neuroimmune regulation during intestinal development and homeostasis. Nat. Immunol. 18, 116–122 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Veiga-Fernandes, H. & Artis, D. Neuronal-immune system cross-talk in homeostasis. Science 359, 1465–1466 (2018).

    Article  PubMed  Google Scholar 

  3. Pavlov, V. A., Chavan, S. S. & Tracey, K. J. Molecular and functional neuroscience in immunity. Annu. Rev. Immunol. 36, 783–812 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baral, P., Udit, S. & Chiu, I. M. Pain and immunity: implications for host defence. Nat. Rev. Immunol. 19, 433–447 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cell treats streptococcal invasive infection. Cell 173, 1083–1097.e22 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Meseguer, V. et al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat. Commun. 5, 3125 (2014).

    Article  PubMed  Google Scholar 

  8. Xu, Z.-Z. et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat. Med. 21, 1326–1331 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ochoa-Cortes, F. et al. Bacterial cell products signal to mouse colonic nociceptive dorsal root ganglia neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G723–G732 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maruyama, K. et al. Nociceptors boost the resolution of fungal osteoinflammation via the TRP channel–CGRP–Jdp2 axis. Cell Rep. 19, 2730–2742 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Ruhl, C. R. et al. Mycobacterium tuberculosis sulfolipid-1 activates nociceptive neurons and induces cough. Cell 181, 293–305.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li, F. et al. Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem. Cell 184, 3762–3773.e10 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation — the peripheral nervous system’s role in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Baral, P. et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat. Med. 24, 417–426 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cohen, J. A. et al. Cutaneous TRPV1+ neurons trigger protective innate type 17 anticipatory immunity. Cell 178, 919–932.e14 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Filtjens, J. et al. Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection. Nat. Commun. 12, 2936 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Perner, C. et al. Substance P release by sensory neurons triggers dendritic cell migration and initiates the type-2 immune response to allergens. Immunity 53, 1063–1077.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ding, W. et al. Calcitonin gene-related peptide-exposed endothelial cells bias Ag presentation to CD4+ T cells toward a TH17 response. J. Immunol. 196, 2181–2194 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Mikami, N. et al. Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T cell functions. J. Immunol. 186, 6886–6893 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Ding, W. et al. Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward TH17 cells. Eur. J. Immunol. 42, 901–911 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Hoeffel, G. et al. Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions. Nature 594, 94–99 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Siiskonen, H. & Harvima, I. Mast cells and sensory nerves contribute to neurogenic inflammation and pruritus in chronic skin inflammation. Front. Cell. Neurosci. 13, 422 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Buhner, S. & Schemann, M. Mast cell–nerve axis with a focus on the human gut. Biochim. Biophys. Acta 1822, 85–92 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. McNeil, B. D. et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519, 237–241 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Green, D. P., Limjunyawong, N., Gour, N., Pundir, P. & Dong, X. A mast-cell-specific receptor mediates neurogenic inflammation and pain. Neuron 101, 412–420.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Serhan, N. et al. House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation. Nat. Immunol. 20, 1435–1443 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Varricchi, G. et al. Heterogeneity of human mast cells with respect to MRGPRX2 receptor expression and function. Front. Cell. Neurosci. 13, 299 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hökfelt, T., Pernow, B. & Wahren, J. Substance P: a pioneer amongst neuropeptides. J. Intern. Med. 249, 27–40 (2001).

    Article  PubMed  Google Scholar 

  31. Zieglgänsberger, W. Substance P and pain chronicity. Cell Tissue Res. 375, 227–241 (2019).

    Article  PubMed  Google Scholar 

  32. Zhang, S. et al. Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis. Cell 184, 2151–2166.e16 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Huang, S. et al. Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential. Cell 184, 441–459.e25 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Caceres, A. I. et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Natl Acad. Sci. USA 106, 9099–9104 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Talbot, S. et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87, 341–354 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tränkner, D., Hahne, N., Sugino, K., Hoon, M. A. & Zuker, C. Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proc. Natl Acad. Sci. USA 111, 11515–11520 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lai, N. Y. et al. Gut-innervating nociceptor neurons regulate Peyer’s patch microfold cells and SFB levels to mediate salmonella host defense. Cell 180, 33–49.e22 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Sharma, N. et al. The emergence of transcriptional identity in somatosensory neurons. Nature 577, 392–398 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Romano, T. A., Felten, S. Y., Felten, D. L. & Olschowka, J. A. Neuropeptide-Y innervation of the rat spleen: another potential immunomodulatory neuropeptide. Brain Behav. Immun. 5, 116–131 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Bjurholm, A., Kreicbergs, A., Terenius, L., Goldstein, M. & Schultzberg, M. Neuropeptide Y-, tyrosine hydroxylase- and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J. Auton. Nerv. Syst. 25, 119–125 (1988).

    Article  CAS  PubMed  Google Scholar 

  41. Pardini, B. J., Jones, S. B. & Filkins, J. P. Cardiac and splenic norepinephrine turnovers in endotoxic rats. Am. J. Physiol. 245, H276–283 (1983).

    CAS  PubMed  Google Scholar 

  42. MacNeil, B. J., Jansen, A. H., Greenberg, A. H. & Nance, D. M. Activation and selectivity of splenic sympathetic nerve electrical activity response to bacterial endotoxin. Am. J. Physiol. 270, R264–270 (1996).

    CAS  PubMed  Google Scholar 

  43. Tang, Y., Shankar, R., Gamelli, R. & Jones, S. Dynamic norepinephrine alterations in bone marrow: evidence of functional innervation. J. Neuroimmunol. 96, 182–189 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Nance, D. M. & Sanders, V. M. Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav. Immun. 21, 736–745 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kin, N. W. & Sanders, V. M. It takes nerve to tell T and B cells what to do. J. Leukoc. Biol. 79, 1093–1104 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Moriyama, S. et al. β2-Adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359, 1056 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Scanzano, A. & Cosentino, M. Adrenergic regulation of innate immunity: a review. Front. Pharmacol. 6, 171 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Marino, F. & Cosentino, M. Adrenergic modulation of immune cells: an update. Amino Acids 45, 55–71 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Woiciechowsky, C. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat. Med. 4, 808–813 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. 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. 62, 2046–2050 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Maestroni, G. J. M. & Mazzola, P. Langerhans cells β2-adrenoceptors: role in migration, cytokine production, TH priming and contact hypersensitivity. J. Neuroimmunol. 144, 91–99 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Yu, X.-Y. et al. Evidence for coexistence of three β-adrenoceptor subtypes in human peripheral lymphocytes. Clin. Pharmacol. Ther. 81, 654–658 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Kavelaars, A. Regulated expression of α-1 adrenergic receptors in the immune system. Brain. Behav. Immun. 16, 799–807 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Lorton, D. & Bellinger, D. L. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int. J. Mol. Sci. 16, 5635–5665 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Körner, A. et al. Sympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A. Nat. Commun. 10, 633 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Matheis, F. et al. Adrenergic signaling in muscularis macrophages limits infection-induced neuronal loss. Cell 180, 64–78.e16 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nevin, J. T., Moussa, M., Corwin, W. L., Mandoiu, I. I. & Srivastava, P. K. Sympathetic nervous tone limits the development of myeloid-derived suppressor cells. Sci. Immunol. 5, eaay9368 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Felten, D. L., Felten, S. Y., Carlson, S. L., Olschowka, J. A. & Livnat, S. Noradrenergic and peptidergic innervation of lymphoid tissue. J. Immunol. 135, 755s–765s (1985).

    CAS  PubMed  Google Scholar 

  60. 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. 52, 595–638 (2000).

    CAS  PubMed  Google Scholar 

  61. Nakai, A., Hayano, Y., Furuta, F., Noda, M. & Suzuki, K. Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. J. Exp. Med. 211, 2583–2598 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Devi, S. et al. Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses. Immunity 54, 1219–1230.e7 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Sloan, E. K., Tarara, R. P., Capitanio, J. P. & Cole, S. W. Enhanced replication of simian immunodeficiency virus adjacent to catecholaminergic varicosities in primate lymph nodes. J. Virol. 80, 4326–4335 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen, C.-S. et al. Loss of direct adrenergic innervation after peripheral nerve injury causes lymph node expansion through IFN-γ. J. Exp. Med. 218, e20202377 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Grebe, K. M. et al. Sympathetic nervous system control of anti-influenza CD8+ T cell responses. Proc. Natl Acad. Sci. USA 106, 5300–5305 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 334, 101 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Zhang, Y. et al. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J. Neurosci. 33, 12970–12981 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lucin, K. M., Sanders, V. M., Jones, T. B., Malarkey, W. B. & Popovich, P. G. Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp. Neurol. 207, 75–84 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ueno, M., Ueno-Nakamura, Y., Niehaus, J., Popovich, P. G. & Yoshida, Y. Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury. Nat. Neurosci. 19, 784–787 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Arima, Y. et al. Regional neural activation defines a gateway for autoreactive T cells to cross the blood–brain barrier. Cell 148, 447–457 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Alaniz, R. C. et al. Dopamine β-hydroxylase deficiency impairs cellular immunity. Proc. Natl Acad. Sci. USA 96, 2274–2278 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rice, P. A., Boehm, G. W., Moynihan, J. A., Bellinger, D. L. & Stevens, S. Y. Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes. J. Neuroimmunol. 114, 19–27 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Madden, K. S., Felten, S. Y., Felten, D. L., Sundaresan, P. R. & Livnat, S. Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav. Immun. 3, 72–89 (1989).

    Article  CAS  PubMed  Google Scholar 

  75. Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Su, X., Matthay, M. A. & Malik, A. B. Requisite role of the cholinergic α7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J. Immunol. 184, 401–410 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. van Westerloo, D. J. et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 130, 1822–1830 (2006).

    Article  PubMed  Google Scholar 

  79. Ghia, J. E., Blennerhassett, P., Kumar-Ondiveeran, H., Verdu, E. F. & Collins, S. M. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131, 1122–1130 (2006).

    Article  PubMed  Google Scholar 

  80. Inoue, T. et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J. Clin. Invest. 126, 1939–1952 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Uni, R. et al. Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration. Sci. Rep. 10, 9472 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Guarini, S. et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107, 1189–1194 (2003).

    Article  PubMed  Google Scholar 

  83. Mioni, C. et al. Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats. Crit. Care Med. 33, 2621–2628 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Huston, J. M. et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 203, 1623–1628 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rosas-Ballina, M. et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl Acad. Sci. USA 105, 11008–11013 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gautron, L. et al. Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen. J. Comp. Neurol. 521, 3741–3767 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Carnevale, D. et al. A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication. Nat. Commun. 7, 13035 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mina-Osorio, P. et al. Neural signaling in the spleen controls B-cell responses to blood-borne antigen. Mol. Med. 18, 618–627 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Berthoud, H.-R. & Powley, T. L. Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia. J. Auton. Nerv. Syst. 42, 153–169 (1993).

    Article  CAS  PubMed  Google Scholar 

  92. Berthoud, H. R. & Powley, T. L. 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 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. 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. 439, 1–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Bratton, B. O. et al. Neural regulation of inflammation: no neural connection from the vagus to splenic sympathetic neurons. Exp. Physiol. 97, 1180–1185 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Martelli, D., Yao, S. T., McKinley, M. J. & McAllen, R. M. Reflex control of inflammation by sympathetic nerves, not the vagus. J. Physiol. 592, 1677–1686 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Martelli, D., Yao, S. T., Mancera, J., McKinley, M. J. & McAllen, R. M. Reflex control of inflammation by the splanchnic anti-inflammatory pathway is sustained and independent of anesthesia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R1085–1091 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Occhinegro, A. et al. The endogenous inflammatory reflex inhibits the inflammatory response to different immune challenges in mice. Brain Behav. Immun. 97, 371–175 (2021).

    Article  CAS  PubMed  Google Scholar 

  98. Komegae, E. N. et al. Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway. Brain Behav. Immun. 73, 441–449 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Murray, K., Rude, K. M., Sladek, J. & Reardon, C. Divergence of neuroimmune circuits activated by afferent and efferent vagal nerve stimulation in the regulation of inflammation. J. Physiol. 599, 2075–2084 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Martelli, D., Farmer, D. G. S., McKinley, M. J., Yao, S. T. & McAllen, R. M. Anti-inflammatory reflex action of splanchnic sympathetic nerves is distributed across abdominal organs. Am. J. Physiol. Regul. Integr. Comp. Physiol. 316, R235–R242 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Abe, C. et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20, 700–707 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020).

    Article  CAS  PubMed  Google Scholar 

  103. Ramirez, V. T. et al. T-cell derived acetylcholine aids host defenses during enteric bacterial infection with Citrobacter rodentium. PLoS Pathog. 15, e1007719 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Olofsson, P. S. et al. α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol. Med. Camb. Mass. 18, 539–543 (2012).

    CAS  PubMed  Google Scholar 

  105. Cox, M. A. et al. Choline acetyltransferase-expressing T cells are required to control chronic viral infection. Science 363, 639–644 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Matteoli, G. et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 63, 938–948 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Dalli, J., Colas, R. A., Arnardottir, H. & Serhan, C. N. Vagal regulation of Group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity 46, 92–105 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mirakaj, V., Dalli, J., Granja, T., Rosenberger, P. & Serhan, C. N. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J. Exp. Med. 211, 1037–1048 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Koopman, F. A. et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 113, 8284–8289 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bonaz, B. et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol. Motil. 28, 948–953 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Sinniger, V. et al. A 12-month pilot study outcomes of vagus nerve stimulation in Crohn’s disease. Neurogastroenterol. Motil. 32, e13911 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Johnson, R. L. & Wilson, C. G. A review of vagus nerve stimulation as a therapeutic intervention. J. Inflamm. Res. 11, 203–213 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415.e13 (2018).

    Article  PubMed  Google Scholar 

  115. Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Klose, C. S. N. et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549, 282–286 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Xu, H. et al. Transcriptional atlas of intestinal immune cells reveals that neuropeptide α-CGRP modulates group 2 innate lymphoid cell responses. Immunity 51, 696–708.e9 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wallrapp, A. et al. Calcitonin gene-related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses. Immunity 51, 709–723.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Nagashima, H. et al. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity 51, 682–695.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Talbot, J. et al. Feeding-dependent VIP neuron–ILC3 circuit regulates the intestinal barrier. Nature 579, 575–580 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Seillet, C. et al. The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity. Nat. Immunol. 21, 168–177 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Grubišić, V. et al. Enteric glia modulate macrophage phenotype and visceral sensitivity following inflammation. Cell Rep. 32, 108100 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Bush, T. G. et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93, 189–201 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Cornet, A. et al. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn’s disease? Proc. Natl Acad. Sci. USA 98, 13306–13311 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yan, Y. et al. Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut. Immunity 54, 499–513.e5 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Jarret, A. et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 180, 50–63.e12 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Knoop, K. A., McDonald, K. G., McCrate, S., McDole, J. R. & Newberry, R. D. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol. 8, 198–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Stead, R. H. et al. Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc. Natl Acad. Sci. USA 84, 2975–2979 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Stead, R. H., Dixon, M. F., Bramwell, N. H., Riddell, R. H. & Bienenstock, J. Mast cells are closely apposed to nerves in the human gastrointestinal mucosa. Gastroenterology 97, 575–585 (1989).

    Article  CAS  PubMed  Google Scholar 

  132. Barbara, G. et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693–702 (2004).

    Article  PubMed  Google Scholar 

  133. Saloman, J. L. et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl Acad. Sci. USA 113, 3078–3083 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Sousa-Valente, J. & Brain, S. D. A historical perspective on the role of sensory nerves in neurogenic inflammation. Semin. Immunopathol. 40, 229–236 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lewis, T. Vascular reactions of the skin to injury. Part 1. React. stroking; urticaria factitia. Heart 11, 119–140 (1924).

    Google Scholar 

  137. No authors listed]. Pharmacology and nerve endings: first dixon memorial lecture by Sir Henry Dale. Br. Med. J. 2, 1161–1163 (1934).

    Article  Google Scholar 

  138. Russell, F. A., King, R., Smillie, S.-J., Kodji, X. & Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94, 1099–1142 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Webster, J. I., Tonelli, L. & Sternberg, E. M. Neuroendocrine regulation of immunity. Annu. Rev. Immunol. 20, 125–163 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Gaykema, R. P. et al. Bacterial endotoxin induces fos immunoreactivity in primary afferent neurons of the vagus nerve. Neuroimmunomodulation 5, 234–240 (1998).

    Article  CAS  PubMed  Google Scholar 

  141. Goehler, L. E. et al. Interleukin-1β in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J. Neurosci. 19, 2799–2806 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Goehler, L. E. et al. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton. Neurosci. Basic Clin. 85, 49–59 (2000).

    Article  CAS  Google Scholar 

  143. Steinberg, B. E. et al. Cytokine-specific neurograms in the sensory vagus nerve. Bioelectron. Med. 3, 7–17 (2016).

    Article  PubMed  Google Scholar 

  144. Pavlov, V. A. & Tracey, K. J. The cholinergic anti-inflammatory pathway. Brain Behav. Immun. 19, 493–499 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Bellinger, D. L. et al. Sympathetic modulation of immunity: relevance to disease. Cell. Immunol. 252, 27–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. & Lotze, M. T. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158–175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Geissmann, F. et al. Development of monocytes, macrophages and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Jakubzick, C. V., Randolph, G. J. & Henson, P. M. Monocyte differentiation and antigen-presenting functions. Nat. Rev. Immunol. 17, 349–362 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Doebel, T., Voisin, B. & Nagao, K. Langerhans cells — the macrophage in dendritic cell clothing. Trends Immunol. 38, 817–828 (2017).

    Article  CAS  PubMed  Google Scholar 

  150. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Stone, K. D., Prussin, C. & Metcalfe, D. D. IgE, mast cells, basophils, and eosinophils. J. Allergy Clin. Immunol. 125, S73–S80 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    Article  CAS  PubMed  Google Scholar 

  153. Bonilla, F. A. & Oettgen, H. C. Adaptive immunity. J. Allergy Clin. Immunol. 125, S33–S40 (2010).

    Article  PubMed  Google Scholar 

  154. Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Godfrey, D. I., Uldrich, A. P., McCluskey, J., Rossjohn, J. & Moody, D. B. The burgeoning family of unconventional T cells. Nat. Immunol. 16, 1114–1123 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I.M.C.’s laboratory received funding from the National Institutes of Health (NIH) (R01DK127257, R01AI130019), Chan-Zuckerberg Initiative, Food Allergy Science Initiative, Kenneth Rainin Foundation, GSK Pharmaceuticals, Abbvie Pharmaceuticals and Burroughs Wellcome Fund. S.U. received support from the NIH under T32 AI007061.

Author information

Authors and Affiliations

  1. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA

    Swalpa Udit, Kimbria Blake & Isaac M. Chiu

Authors
  1. Swalpa Udit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimbria Blake
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isaac M. Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.U. researched the data for the article. S.U., K.B. and I.M.C. made substantial contributions to the discussion of content, wrote the article and reviewed/edited the article before submission.

Corresponding author

Correspondence to Isaac M. Chiu.

Ethics declarations

Competing interests

S.U. is a current employee of Vertex Pharmaceuticals and may own company stock. K.B. is a current employee of Genoskin Inc. I.M.C. serves on scientific advisory boards for GSK Pharmaceuticals and Limm Therapeutics. His laboratory receives research support from Abbvie Pharmaceuticals, GSK Pharmaceuticals and Moderna Inc.

Additional information

Peer review information

Nature Reviews Neuroscience thanks N. Gaudenzio, D. Kaplan, K. Tracey and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Immunological Genome Project: https://www.immgen.org/

Glossary

Host defence

The mechanisms by which an organism protects against infection, including natural barriers, inflammatory reactions, non-specific innate immune responses and specific adaptive immune responses.

Blood–brain barrier

The barrier formed by the CNS capillary endothelium, which restricts non-selective transport of substances, including pathogens and cells, from circulating blood into the CNS extracellular fluid.

Autoimmunity

The conditions in which immune system responses are directed against normal components of an organism or self-antigens.

Barrier tissues

The bodily tissues that interface with the external world and represent both a physical and an immunological barrier between the host and the environment.

Optogenetics

Experimental techniques that allow the modulation of excitable cells using light via genetically specified expression of opsins, or light-activated proteins, in the cellular population of interest with resulting cellular excitation or silencing upon stimulation with light.

Cytokines

A category of small proteins expressed by various cells; cytokines have immunomodulating roles and include chemokines, lymphokines, interferons and interleukins.

Chemokines

A class of chemotactic cytokines that function as chemoattractants to induce the directional migration of other cells, notably leukocytes.

Neuropeptide

A short-chain peptide synthesized and released by neurons which functions to signal to neuronal substrates.

Axonal reflexes

Responses through which stimulation of one axon branch results in a nerve impulse that travels back at branching points to other axonal branches, resulting in stimulation of collateral branches.

T helper cells

A type of adaptive immune cell, also known as CD4-expressing (CD4+) T cells, whose main function is the activation, recruitment and polarization of other immune cells.

Mast cell degranulation

An event that occurs in response to mast cell activation, in which preformed mediators from cytoplasmic granules are released into surrounding tissue.

Lymphoid tissues

A set of tissues that consist of primary lymphoid tissues (which include the bone marrow and thymus) in which lymphocyte production and development takes place, and secondary lymphoid tissues (which include the lymph nodes, spleen, Peyer’s patches and mucosa-associated lymphoid tissue (MALT)) where naive mature lymphocytes come into contact with antigens to initiate adaptive immune responses.

Resolution

An active and highly regulated phase of the immune response which acts to counter-regulate inflammation and restore tissue homeostasis.

Type 2 inflammation

An inflammatory pathway characterized by activation of T helper 2 cells (TH2 cells), type 2 innate lymphoid cells (ILC2s), secretion of particular cytokines including interleukin-4 (IL-4), IL-5 and IL-13, IgE production and downstream activation of other immune cells such as mast cells or basophils.

Lymphocyte trafficking

The process by which lymphocytes adhere to and migrate across vascular endothelium to a tissue or site of inflammation.

Antimicrobial peptide

A class of protein secreted by cells of the innate immune system that has broad and potent microbicidal properties and includes peptides with antibacterial, antifungal and antiviral properties.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Udit, S., Blake, K. & Chiu, I.M. Somatosensory and autonomic neuronal regulation of the immune response. Nat Rev Neurosci 23, 157–171 (2022). https://doi.org/10.1038/s41583-021-00555-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-021-00555-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing