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.
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Rankin, L. C. & Artis, D. Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell 173, 554–567 (2018).
Veiga-Fernandes, H. & Freitas, A. A. The s(c)ensory immune system theory. Trends Immunol. 38, 777–788 (2017).
Besedovsky, H. et al. The immune response evokes changes in brain noradrenergic neurons. Science 221, 564–566 (1983).
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).
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).
Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010).
Veiga-Fernandes, H. & Pachnis, V. Neuroimmune regulation during intestinal development and homeostasis. Nat. Immunol. 18, 116–122 (2017).
Godinho-Silva, C., Cardoso, F. & Veiga-Fernandes, H. Neuro-immune cell units: a new paradigm in physiology. Annu. Rev. Immunol. 37, 19–46 (2019).
Veiga-Fernandes, H. & Artis, D. Neuronal–immune system cross-talk in homeostasis. Science 359, 1465–1466 (2018).
Veiga-Fernandes, H. & Mucida, D. Neuro-immune interactions at barrier surfaces. Cell 165, 801–811 (2016).
Chesne, J., Cardoso, V. & Veiga-Fernandes, H. Neuro-immune regulation of mucosal physiology. Mucosal Immunol. 12, 10–20 (2019).
Kabashima, K., Honda, T., Ginhoux, F. & Egawa, G. The immunological anatomy of the skin. Nat. Rev. Immunol. 19, 19–30 (2019).
Oetjen, L. K. et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171, 217–228 (2017).
Gupta, K. & Harvima, I. T. Mast cell–neural interactions contribute to pain and itch. Immunol. Rev. 282, 168–187 (2018).
Serhan, N. et al. House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation. Nat. Immunol. 20, 1435–1443 (2019).
Kolter, J. et al. A subset of skin macrophages contributes to the surveillance and regeneration of local nerves. Immunity 50, 1482–1497 (2019).
Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats Streptococcal invasive infection. Cell 173, 1083–1097 (2018).
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.
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).
Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).
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).
Nassenstein, C., Kutschker, J., Tumes, D. & Braun, A. Neuro-immune interaction in allergic asthma: role of neurotrophins. Biochem. Soc. Trans. 34, 591–593 (2006).
Chesne, J. et al. IL-17 in severe asthma. Where do we stand? Am. J. Respir. Crit. Care Med. 190, 1094–1101 (2014).
Foster, S. L., Seehus, C. R., Woolf, C. J. & Talbot, S. Sense and immunity: context-dependent neuro-immune interplay. Front. Immunol. 8, 1463 (2017).
Lee, L. Y. & Yu, J. Sensory nerves in lung and airways. Compr. Physiol. 4, 287–324 (2014).
McGovern, A. E. & Mazzone, S. B. Neural regulation of inflammation in the airways and lungs. Auton. Neurosci. 182, 95–101 (2014).
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).
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).
Jacoby, D. B., Costello, R. M. & Fryer, A. D. Eosinophil recruitment to the airway nerves. J. Allergy Clin. Immunol. 107, 211–218 (2001).
Cyphert, J. M. et al. Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction. J. Immunol. 182, 7430–7439 (2009).
Voisin, T., Bouvier, A. & Chiu, I. M. Neuro-immune interactions in allergic diseases: novel targets for therapeutics. Int. Immunol. 29, 247–261 (2017).
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).
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).
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).
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).
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).
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.
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.
Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017).
Klose, C. S. N. et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549, 282–286 (2017).
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.
Galle-Treger, L. et al. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity. Nat. Commun. 7, 13202 (2016).
Sui, P. et al. Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360, eaan8546 (2018).
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).
Nagashima, H. et al. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity 51, 682–695 (2019).
Wallrapp, A. et al. Calcitonin gene-related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses. Immunity 51, 709–723 (2019).
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).
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).
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).
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).
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).
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).
Furness, J. B. Types of neurons in the enteric nervous system. J. Auton. Nerv. Syst. 81, 87–96 (2000).
Matteoli, G. et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 63, 938–948 (2014).
Yoo, B. B. & Mazmanian, S. K. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46, 910–926 (2017).
Kioussis, D. & Pachnis, V. Immune and nervous systems: more than just a superficial similarity? Immunity 31, 705–710 (2009).
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).
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).
Tamura, K. & Wood, J. D. Effects of prolonged exposure to histamine on guinea pig intestinal neurons. Dig. Dis. Sci. 37, 1084–1088 (1992).
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).
Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat. Med. 6, 151–158 (2000).
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).
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).
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).
Barbara, G. et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132, 26–37 (2007).
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).
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).
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).
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).
Bain, C. C. & Mowat, A. M. Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 260, 102–117 (2014).
Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).
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.
Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).
Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).
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.
Veiga-Fernandes, H. et al. Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature 446, 547–551 (2007).
Patel, A. et al. Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems. Sci. Signal. 5, ra55 (2012).
Fonseca-Pereira, D. et al. The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514, 98–101 (2014).
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).
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.
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).
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).
Moriyama, S. et al. β2-Adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359, 1056–1061 (2018).
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).
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.
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).
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.
Kim, S. et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528–532 (2017).
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.
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.
Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817–829 (2015).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).
Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).
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).
Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 357, 806–810 (2017).
Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).
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).
Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).
Faraco, G. et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat. Neurosci. 21, 240–249 (2018).
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).
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).
Marin, I. A. et al. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci. Rep. 7, 43859 (2017).
Poutahidis, T. et al. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLOS ONE 8, e78898 (2013).
Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).
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).
Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).
Becher, B., Spath, S. & Goverman, J. Cytokine networks in neuroinflammation. Nat. Rev. Immunol. 17, 49–59 (2017).
Kim, T. K. et al. Local interleukin-18 system in the basolateral amygdala regulates susceptibility to chronic stress. Mol. Neurobiol. 54, 5347–5358 (2017).
Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).
Garber, C. et al. Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat. Immunol. 19, 151–161 (2018).
Zhu, P. J. et al. Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell 147, 1384–1396 (2011).
Filiano, A. J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).
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).
Brombacher, T. M. et al. IL-13-mediated regulation of learning and memory. J. Immunol. 198, 2681–2688 (2017).
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.
Ribeiro, M. et al. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci. Immunol. 4, eaay5199 (2019).
Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019).
Ito, M. et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246–250 (2019).
Kigerl, K. A. et al. Gut dysbiosis impairs recovery after spinal cord injury. J. Exp. Med. 213, 2603–2620 (2016).
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.
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).
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).
Liesz, A. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009).
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).
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.
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).
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.
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).
Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516 (2018).
Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).
Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).
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).
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).
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).
Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016).
Shin Yim, Y. et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549, 482–487 (2017).
Torres-Rosas, R. et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat. Med. 20, 291–295 (2014).
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.).
The authors declare no competing interests.
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.
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Huh, J.R., Veiga-Fernandes, H. Neuroimmune circuits in inter-organ communication. Nat Rev Immunol 20, 217–228 (2020). https://doi.org/10.1038/s41577-019-0247-z