Skip to main content

Thank you for visiting 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.

Neuroimmune circuits in inter-organ communication


Studies in recent years have uncovered the crucial function of neuroimmune interactions in maintaining tissue homeostasis and protection. Immune and neuronal cells are often colocalized at defined anatomical sites, forming neuroimmune cell units, where both cell types coordinate their responses. In addition, even when located at distant sites, neuronal cells can receive signals from and provide signals to peripheral immune cells. As such, neuroimmune interactions are found across multiple organs and have recently emerged as important regulators of physiology. In this Review, we focus on the impact of bidirectional neuroimmune interactions in tissue biology, organ physiology and embryonic development. Finally, we explore how this fast-evolving field is redefining the tenets of inter-organ and intergenerational communications.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Neuroimmune crosstalk in the skin.
Fig. 2: Neuroimmune crosstalk in the lungs.
Fig. 3: Neuroimmune crosstalk in the gut.
Fig. 4: The gut–brain axis and the maternal gut–fetal brain axis.


  1. 1.

    Rankin, L. C. & Artis, D. Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell 173, 554–567 (2018).

    CAS  PubMed  Google Scholar 

  2. 2.

    Veiga-Fernandes, H. & Freitas, A. A. The s(c)ensory immune system theory. Trends Immunol. 38, 777–788 (2017).

    CAS  PubMed  Google Scholar 

  3. 3.

    Besedovsky, H. et al. The immune response evokes changes in brain noradrenergic neurons. Science 221, 564–566 (1983).

    CAS  PubMed  Google Scholar 

  4. 4.

    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).

    CAS  PubMed  Google Scholar 

  5. 5.

    Matsunaga, H. et al. Physiological stress exacerbates murine colitis by enhancing proinflammatory cytokine expression that is dependent on IL-18. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G555–G564 (2011).

    CAS  PubMed  Google Scholar 

  6. 6.

    Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

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

    CAS  PubMed  Google Scholar 

  8. 8.

    Godinho-Silva, C., Cardoso, F. & Veiga-Fernandes, H. Neuro-immune cell units: a new paradigm in physiology. Annu. Rev. Immunol. 37, 19–46 (2019).

    CAS  PubMed  Google Scholar 

  9. 9.

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

    PubMed  Google Scholar 

  10. 10.

    Veiga-Fernandes, H. & Mucida, D. Neuro-immune interactions at barrier surfaces. Cell 165, 801–811 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Chesne, J., Cardoso, V. & Veiga-Fernandes, H. Neuro-immune regulation of mucosal physiology. Mucosal Immunol. 12, 10–20 (2019).

    CAS  PubMed  Google Scholar 

  12. 12.

    Kabashima, K., Honda, T., Ginhoux, F. & Egawa, G. The immunological anatomy of the skin. Nat. Rev. Immunol. 19, 19–30 (2019).

    CAS  PubMed  Google Scholar 

  13. 13.

    Oetjen, L. K. et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171, 217–228 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gupta, K. & Harvima, I. T. Mast cell–neural interactions contribute to pain and itch. Immunol. Rev. 282, 168–187 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

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

    CAS  PubMed  Google Scholar 

  16. 16.

    Kolter, J. et al. A subset of skin macrophages contributes to the surveillance and regeneration of local nerves. Immunity 50, 1482–1497 (2019).

    CAS  PubMed  Google Scholar 

  17. 17.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    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). This study demonstrates that nociceptor neurons suppress immunity to bacterial lung infection via inhibition of neutrophil and γδ T cell recruitment.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Audrit, K. J., Delventhal, L., Aydin, O. & Nassenstein, C. The nervous system of airways and its remodeling in inflammatory lung diseases. Cell Tissue Res. 367, 571–590 (2017).

    PubMed  Google Scholar 

  22. 22.

    Nassenstein, C., Kutschker, J., Tumes, D. & Braun, A. Neuro-immune interaction in allergic asthma: role of neurotrophins. Biochem. Soc. Trans. 34, 591–593 (2006).

    CAS  PubMed  Google Scholar 

  23. 23.

    Chesne, J. et al. IL-17 in severe asthma. Where do we stand? Am. J. Respir. Crit. Care Med. 190, 1094–1101 (2014).

    CAS  PubMed  Google Scholar 

  24. 24.

    Foster, S. L., Seehus, C. R., Woolf, C. J. & Talbot, S. Sense and immunity: context-dependent neuro-immune interplay. Front. Immunol. 8, 1463 (2017).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lee, L. Y. & Yu, J. Sensory nerves in lung and airways. Compr. Physiol. 4, 287–324 (2014).

    PubMed  Google Scholar 

  26. 26.

    McGovern, A. E. & Mazzone, S. B. Neural regulation of inflammation in the airways and lungs. Auton. Neurosci. 182, 95–101 (2014).

    CAS  PubMed  Google Scholar 

  27. 27.

    Costello, R. W. et al. Localization of eosinophils to airway nerves and effect on neuronal M2 muscarinic receptor function. Am. J. Physiol. 273, L93–L103 (1997).

    CAS  PubMed  Google Scholar 

  28. 28.

    Nilsson, G., Alving, K., Ahlstedt, S., Hokfelt, T. & Lundberg, J. M. Peptidergic innervation of rat lymphoid tissue and lung: relation to mast cells and sensitivity to capsaicin and immunization. Cell Tissue Res. 262, 125–133 (1990).

    CAS  PubMed  Google Scholar 

  29. 29.

    Jacoby, D. B., Costello, R. M. & Fryer, A. D. Eosinophil recruitment to the airway nerves. J. Allergy Clin. Immunol. 107, 211–218 (2001).

    CAS  PubMed  Google Scholar 

  30. 30.

    Cyphert, J. M. et al. Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction. J. Immunol. 182, 7430–7439 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Voisin, T., Bouvier, A. & Chiu, I. M. Neuro-immune interactions in allergic diseases: novel targets for therapeutics. Int. Immunol. 29, 247–261 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Sawatzky, D. A. et al. Eosinophil adhesion to cholinergic nerves via ICAM-1 and VCAM-1 and associated eosinophil degranulation. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L1279–L1288 (2002).

    CAS  PubMed  Google Scholar 

  33. 33.

    Nie, Z., Nelson, C. S., Jacoby, D. B. & Fryer, A. D. Expression and regulation of intercellular adhesion molecule-1 on airway parasympathetic nerves. J. Allergy Clin. Immunol. 119, 1415–1422 (2007).

    CAS  PubMed  Google Scholar 

  34. 34.

    Fryer, A. D. et al. Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J. Clin. Invest. 116, 228–236 (2006).

    CAS  PubMed  Google Scholar 

  35. 35.

    Ansel, J. C., Brown, J. R., Payan, D. G. & Brown, M. A. Substance P selectively activates TNF-α gene expression in murine mast cells. J. Immunol. 150, 4478–4485 (1993).

    CAS  PubMed  Google Scholar 

  36. 36.

    Kulka, M., Sheen, C. H., Tancowny, B. P., Grammer, L. C. & Schleimer, R. P. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 123, 398–410 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013). This work demonstrates that VIP stimulates ILC2s, which in turn regulate eosinophil homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Talbot, S. et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87, 341–354 (2015). This study shows that nociceptor neurons are important regulators of pulmonary allergic reactions.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wallrapp, A. et al. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549, 351–356 (2017). Together with references 39 and 40, this study shows that the neuronal-derived peptide NMU is a uniquely potent activator of ILC2s.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Galle-Treger, L. et al. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity. Nat. Commun. 7, 13202 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Sui, P. et al. Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360, eaan8546 (2018).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Barrios, J. et al. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 31, 4117–4128 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

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

    CAS  PubMed  Google Scholar 

  46. 46.

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

    CAS  PubMed  Google Scholar 

  47. 47.

    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 (2019).

    CAS  PubMed  Google Scholar 

  48. 48.

    Assas, B. M., Pennock, J. I. & Miyan, J. A. Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis. Front. Neurosci. 8, 23 (2014).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Veres, T. Z. et al. Spatial interactions between dendritic cells and sensory nerves in allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 37, 553–561 (2007).

    CAS  PubMed  Google Scholar 

  50. 50.

    Veres, T. Z., Rochlitzer, S. & Braun, A. The role of neuro-immune cross-talk in the regulation of inflammation and remodelling in asthma. Pharmacol. Ther. 122, 203–214 (2009).

    CAS  PubMed  Google Scholar 

  51. 51.

    Veres, T. Z. et al. Dendritic cell–nerve clusters are sites of T cell proliferation in allergic airway inflammation. Am. J. Pathol. 174, 808–817 (2009).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Furness, J. B., Callaghan, B. P., Rivera, L. R. & Cho, H. J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv. Exp. Med. Biol. 817, 39–71 (2014).

    PubMed  Google Scholar 

  53. 53.

    Furness, J. B. Types of neurons in the enteric nervous system. J. Auton. Nerv. Syst. 81, 87–96 (2000).

    CAS  PubMed  Google Scholar 

  54. 54.

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

    CAS  PubMed  Google Scholar 

  55. 55.

    Yoo, B. B. & Mazmanian, S. K. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46, 910–926 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Kioussis, D. & Pachnis, V. Immune and nervous systems: more than just a superficial similarity? Immunity 31, 705–710 (2009).

    CAS  PubMed  Google Scholar 

  57. 57.

    van Diest, S. A., Stanisor, O. I., Boeckxstaens, G. E., de Jonge, W. J. & van den Wijngaard, R. M. Relevance of mast cell–nerve interactions in intestinal nociception. Biochim. Biophys. Acta 1822, 74–84 (2012).

    PubMed  Google Scholar 

  58. 58.

    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).

    CAS  PubMed  Google Scholar 

  59. 59.

    Tamura, K. & Wood, J. D. Effects of prolonged exposure to histamine on guinea pig intestinal neurons. Dig. Dis. Sci. 37, 1084–1088 (1992).

    CAS  PubMed  Google Scholar 

  60. 60.

    Reed, D. E. et al. Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons. J. Physiol. 547, 531–542 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat. Med. 6, 151–158 (2000).

    CAS  PubMed  Google Scholar 

  62. 62.

    Shanahan, F., Denburg, J. A., Fox, J., Bienenstock, J. & Befus, D. Mast cell heterogeneity: effects of neuroenteric peptides on histamine release. J. Immunol. 135, 1331–1337 (1985).

    CAS  PubMed  Google Scholar 

  63. 63.

    Caughey, G. H., Leidig, F., Viro, N. F. & Nadel, J. A. Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J. Pharmacol. Exp. Ther. 244, 133–137 (1988).

    CAS  PubMed  Google Scholar 

  64. 64.

    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).

    PubMed  Google Scholar 

  65. 65.

    Barbara, G. et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132, 26–37 (2007).

    CAS  PubMed  Google Scholar 

  66. 66.

    Buhner, S. et al. Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 137, 1425–1434 (2009).

    CAS  PubMed  Google Scholar 

  67. 67.

    Belai, A., Boulos, P. B., Robson, T. & Burnstock, G. Neurochemical coding in the small intestine of patients with Crohn’s disease. Gut 40, 767–774 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Bai, A., Lu, N., Guo, Y., Chen, J. & Liu, Z. Modulation of inflammatory response via α2-adrenoceptor blockade in acute murine colitis. Clin. Exp. Immunol. 156, 353–362 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Xia, C. M., Colomb, D. G. Jr., Akbarali, H. I. & Qiao, L. Y. Prolonged sympathetic innervation of sensory neurons in rat thoracolumbar dorsal root ganglia during chronic colitis. Neurogastroenterol. Motil. 23, 801-e339 (2011).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Bain, C. C. & Mowat, A. M. Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 260, 102–117 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014). This study shows that macrophages and neurons in the intestinal muscularis interact in a bidirectional manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).

    CAS  PubMed  Google Scholar 

  74. 74.

    Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).

    CAS  PubMed  Google Scholar 

  75. 75.

    Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016). This study indicates that intestinal ILC3s can integrate neuroglia-derived factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Veiga-Fernandes, H. et al. Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature 446, 547–551 (2007).

    CAS  PubMed  Google Scholar 

  77. 77.

    Patel, A. et al. Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems. Sci. Signal. 5, ra55 (2012).

    PubMed  Google Scholar 

  78. 78.

    Fonseca-Pereira, D. et al. The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514, 98–101 (2014).

    CAS  PubMed  Google Scholar 

  79. 79.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Godinho-Silva, C. et al. Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis. Nature 574, 254–258 (2019). This study shows that photonic cues and brain-derived circadian signals are major regulators of intestinal ILC3 homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Wang, Q. et al. Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells. Sci. Immunol. 4, eaay7501 (2019).

    CAS  PubMed  Google Scholar 

  82. 82.

    Teng, F. et al. A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut. Sci. Immunol. 4, eaax1215 (2019).

    CAS  PubMed  Google Scholar 

  83. 83.

    Moriyama, S. et al. β2-Adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359, 1056–1061 (2018).

    CAS  PubMed  Google Scholar 

  84. 84.

    Scott, K. A. et al. Revisiting Metchnikoff: age-related alterations in microbiota–gut–brain axis in the mouse. Brain Behav. Immun. 65, 20–32 (2017).

    PubMed  Google Scholar 

  85. 85.

    Sgritta, M. et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 101, 246–259 (2019). This study reports that gut-residing bacteria affect animal behaviour by stimulating the production of the neuromodulator oxytocin in the brain.

    CAS  PubMed  Google Scholar 

  86. 86.

    Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586–597 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). This study shows that gut bacteria contribute to the proper development of microglia.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Kim, S. et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528–532 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Lammert, C. R. et al. Cutting edge: critical roles for microbiota-mediated regulation of the immune system in a prenatal immune activation model of autism. J. Immunol. 201, 845–850 (2018). Together with reference 88, this study illustrates the critical function of gut bacteria in pregnant dams in promoting neurodevelopmental disorder-like phenotypes in their offspring.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Rojas, O. L. et al. Recirculating intestinal IgA-producing cells regulate neuroinflammation via IL-10. Cell 176, 610–624 (2019). This study shows that IgA-producing B cells can migrate from the gut to the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817–829 (2015).

    CAS  PubMed  Google Scholar 

  92. 92.

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Smits, H. H. et al. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J. Allergy Clin. Immunol. 115, 1260–1267 (2005).

    CAS  PubMed  Google Scholar 

  99. 99.

    Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 357, 806–810 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Kadowaki, A. et al. Gut environment-induced intraepithelial autoreactive CD4+ T cells suppress central nervous system autoimmunity via LAG-3. Nat. Commun. 7, 11639 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    CAS  PubMed  Google Scholar 

  103. 103.

    Faraco, G. et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat. Neurosci. 21, 240–249 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Tabouy, L. et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav. Immun. 73, 310–319 (2018).

    PubMed  Google Scholar 

  105. 105.

    Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011).

    CAS  PubMed  Google Scholar 

  106. 106.

    Marin, I. A. et al. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci. Rep. 7, 43859 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Poutahidis, T. et al. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLOS ONE 8, e78898 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019).

    CAS  PubMed  Google Scholar 

  110. 110.

    Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Becher, B., Spath, S. & Goverman, J. Cytokine networks in neuroinflammation. Nat. Rev. Immunol. 17, 49–59 (2017).

    CAS  PubMed  Google Scholar 

  112. 112.

    Kim, T. K. et al. Local interleukin-18 system in the basolateral amygdala regulates susceptibility to chronic stress. Mol. Neurobiol. 54, 5347–5358 (2017).

    CAS  PubMed  Google Scholar 

  113. 113.

    Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).

    CAS  PubMed  Google Scholar 

  114. 114.

    Garber, C. et al. Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat. Immunol. 19, 151–161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Zhu, P. J. et al. Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell 147, 1384–1396 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Filiano, A. J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Brombacher, T. M. et al. IL-13-mediated regulation of learning and memory. J. Immunol. 198, 2681–2688 (2017).

    CAS  PubMed  Google Scholar 

  119. 119.

    Chen, C. et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). This study uses forward genetic approaches and demonstrates that IL-17 is a neuromodulator that affects animal behaviours.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Ribeiro, M. et al. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci. Immunol. 4, eaay5199 (2019).

    CAS  PubMed  Google Scholar 

  121. 121.

    Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019).

    CAS  PubMed  Google Scholar 

  122. 122.

    Ito, M. et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246–250 (2019).

    CAS  PubMed  Google Scholar 

  123. 123.

    Kigerl, K. A. et al. Gut dysbiosis impairs recovery after spinal cord injury. J. Exp. Med. 213, 2603–2620 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Singh, V. et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J. Neurosci. 36, 7428–7440 (2016). This study demonstrates that the microbiota can determine inflammatory outcomes after stroke.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).

    CAS  PubMed  Google Scholar 

  126. 126.

    Ochoa-Reparaz, J. et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J. Immunol. 185, 4101–4108 (2010).

    CAS  PubMed  Google Scholar 

  127. 127.

    Liesz, A. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009).

    CAS  PubMed  Google Scholar 

  128. 128.

    Shichita, T. et al. Pivotal role of cerebral interleukin-17-producing γδT cells in the delayed phase of ischemic brain injury. Nat. Med. 15, 946–950 (2009).

    CAS  PubMed  Google Scholar 

  129. 129.

    Benakis, C. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat. Med. 22, 516–523 (2016). This study shows that gut-residing γδ T cells can migrate into the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Xu, D. et al. Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy. J. Exp. Med. 215, 1169–1186 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Koren, O. et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470–480 (2012). This study reports that pregnancy alone can induce changes in the gut microbial community of a pregnant female.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Leclercq, S. et al. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat. Commun. 8, 15062 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).

    PubMed  Google Scholar 

  136. 136.

    Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).

    CAS  PubMed  Google Scholar 

  137. 137.

    Shi, L., Fatemi, S. H., Sidwell, R. W. & Patterson, P. H. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23, 297–302 (2003).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J. & Patterson, P. H. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26, 607–616 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Shin Yim, Y. et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549, 482–487 (2017).

    PubMed  Google Scholar 

  141. 141.

    Torres-Rosas, R. et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat. Med. 20, 291–295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by the Simons Foundation Autism Research Initiative (J.R.H.), the Jeongho Kim Neurodevelopmental Research Fund (J.R.H.), the Pew Scholar for Biomedical Sciences (J.R.H.), the US National Institutes of Health (grant R01MH119459) (J.R.H), the European Research Council (647274) (H.V.-F.), the Fundação para a Ciência e Tecnologia Portugal (H.V.-F.) and the Paul G. Allen Frontiers Group (H.V.-F.).

Author information




J.R.H. and H.V.-F. both wrote and edited the manuscript.

Corresponding authors

Correspondence to Jun R. Huh or Henrique Veiga-Fernandes.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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


Substance P

A neuropeptide of 11 amino acids in length belonging to the tachykinin family, formed by differential splicing of the preprotachykinin A gene (TAC1). Substance P is widely distributed throughout the nervous system but has been best appreciated as an important neurotransmitter in nociceptive pathways.

Nociceptor neurons

Sensory neurons that are activated by noxious or damaging stimuli. Nociceptor neurons are classified according to their ability to respond to mechanical, thermal and chemical stimuli. Free nerve endings in the periphery serving as receptive sites extend from neuronal cell bodies in the dorsal root or cranial nerve ganglia.


The neural process of encoding noxious mechanical, thermal and/or chemical stimuli that occurs in afferent fibres, which send signals to the central nervous system.

Cholinergic neurons

Neuronal cells that mostly communicate via the neurotransmitter acetylcholine.

Dorsal root ganglia

The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. These neurons are pseudo-unipolar in nature, meaning that they have one axon with two processes: one peripheral axonal branch that innervates the tissues of the body to receive sensory information and one axonal branch that sends nerve impulses to the spinal cord. Dorsal root ganglia also contain satellite glia and macrophages that can modulate the function of sensory neurons.

Pulmonary neuroendocrine cells

(PNECs). Specialized epithelial cells that are present in the airways. Neuroendocrine cells can be found as solitary cells or associated in cell clusters called pulmonary neuroepithelial bodies. Neuroendocrine cells receive neuronal input that controls the release of endocrine molecules.

Vagus nerve

The nerve that connects the brainstem to the rest of the body. It contributes to the autonomic nervous system, which consists of the parasympathetic and sympathetic arms.

Enteric glial cells

A type of peripheral glia that are similar to astrocytes of the central nervous system. Among other functions, they maintain the structural integrity of the nervous system, provide trophic support to neurons, insulate one neuron from another and can clear debris.

Sympathetic catecholaminergic neurons

Sympathetic neurons are normally assumed to be part of the peripheral nervous system, but many of these neuronal cell bodies are present in the central nervous system. Sympathetic neurons of the spinal cord communicate with peripheral sympathetic neurons. In response to this stimulus, postganglionic neurons release catecholamines that bind adrenergic receptors on target cells inducing ‘fight-or-flight’ responses.

Blood–brain barrier

A physiological barrier between blood vessels and brain parenchyma. The barrier is formed by specialized tight junctions between endothelial cells of the blood vessel wall, which is surrounded by a basement membrane and an additional membrane formed from astrocyte feet and microglial cells, known as the glial limitans.

Aryl hydrocarbon receptor

(AHR). A cytosolic, ligand-dependent transcription factor that translocates to the nucleus following the binding of specific ligands, which include dietary and microbial metabolites. AHR participates in the differentiation of regulatory T cells, T helper 17 (TH17) cells and intraepithelial intestinal γδ T cells, and is required for the secretion of IL-22 by TH17 cells. More recently, AHR has been shown to have crucial roles in the development and function of lymphoid tissue inducer cells and group 3 innate lymphoid cells.


The most abundant type of cell in the brain, named for their characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, such as supporting the formation and pruning of neuronal synapses.

Basolateral amygdala

A brain region extensively studied for its role in fear learning.

Segmented filamentous bacteria

A Gram-positive, spore-forming, non-culturable, Clostridia-related bacterium (provisionally named Candidatus savagella (of the Clostridiaceae family)) that resides in the terminal ileum in direct contact with intestinal epithelial cells and that induces the expression of IL-17A, IL-22 and IgA in the host.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huh, J.R., Veiga-Fernandes, H. Neuroimmune circuits in inter-organ communication. Nat Rev Immunol 20, 217–228 (2020).

Download citation


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