Review Article | Published:

Neuroimmune regulation during intestinal development and homeostasis

Nature Immunology volume 18, pages 116122 (2017) | Download Citation

Abstract

Interactions between the nervous system and immune system are required for organ function and homeostasis. Evidence suggests that enteric neurons and intestinal immune cells share common regulatory mechanisms and can coordinate their responses to developmental challenges and environmental aggressions. These discoveries shed light on the physiology of system interactions and open novel perspectives for therapy designs that target underappreciated neurological–immunological commonalities. Here we highlight findings that address the importance of neuroimmune cell units (NICUs) in intestinal development, homeostasis and disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Neuroimmune interactions at barrier surfaces. Cell 165, 801–811 (2016).

  2. 2.

    Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).

  3. 3.

    et al. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. 36, 578–604 (2015).

  4. 4.

    , & Neuroimmunity: physiology and pathology. Annu. Rev. Immunol. 34, 421–447 (2016).

  5. 5.

    , & Cellular organization of neuroimmune interactions in the gastrointestinal tract. Trends Immunol. 37, 487–501 (2016).

  6. 6.

    , , & Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360–373 (2015).

  7. 7.

    Multifaceted interactions between adaptive immunity and the central nervous system. Science 353, 766–771 (2016).

  8. 8.

    , , & Development of the intrinsic and extrinsic innervation of the gut. Dev. Biol. 417, 158–167 (2016).

  9. 9.

    , , , & The gut as a sensory organ. Nat. Rev. Gastroenterol. Hepatol. 10, 729–740 (2013).

  10. 10.

    & Innervation of the gastrointestinal tract: patterns of aging. Auton. Neurosci. 136, 1–19 (2007).

  11. 11.

    , , & Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia 63, 229–241 (2015).

  12. 12.

    & Novel functional roles for enteric glia in the gastrointestinal tract. Nat. Rev. Gastroenterol. Hepatol. 9, 625–632 (2012).

  13. 13.

    et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015).By genetic lineage tracing, the authors reveal that the network of mucosal glial cells is continuously renewed, in a microbiota-dependent manner, by incoming glial cells that originate in the plexi of the gut wall.

  14. 14.

    , & Neurogenic regulation of dendritic cells in the intestine. Biochem. Pharmacol. 80, 2002–2008 (2010).

  15. 15.

    et al. Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G976–G987 (2011).

  16. 16.

    & The migration of neural crest cells to the wall of the digestive tract in avian embryo. J. Embryol. Exp. Morphol. 30, 31–48 (1973).

  17. 17.

    & The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J. Comp. Neurol. 101, 515–541 (1954).

  18. 18.

    & The pattern of neural crest advance in the cecum and colon. Dev. Biol. 287, 125–133 (2005).

  19. 19.

    et al. Dynamics of neural crest-derived cell migration in the embryonic mouse gut. Dev. Biol. 270, 455–473 (2004).

  20. 20.

    et al. Colonizing while migrating: how do individual enteric neural crest cells behave? BMC Biol. 12, 23 (2014).

  21. 21.

    , & Building a second brain in the bowel. J. Clin. Invest. 125, 899–907 (2015).

  22. 22.

    & Development of enteric neuron diversity. J. Cell. Mol. Med. 13, 1193–1210 (2009).

  23. 23.

    et al. Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J. Clin. Invest. 121, 3412–3424 (2011).

  24. 24.

    , & Acquisition of neuronal and glial markers by neural crest-derived cells in the mouse intestine. J. Comp. Neurol. 456, 1–11 (2003).

  25. 25.

    et al. The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. Development 130, 2525–2534 (2003).

  26. 26.

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

  27. 27.

    et al. Tyrosine kinase receptor RET is a key regulator of Peyer's patch organogenesis. Nature 446, 547–551 (2007).This study identifies a population of RET-expressing CD11c+ hematopoietic cells in the fetal intestine. Activation of RET drives enteric lymphoid organogenesis, while lack of RET results in PP developmental failure.

  28. 28.

    , & Stroma cell priming in enteric lymphoid organ morphogenesis. Front. Immunol. 3, 219 (2012).

  29. 29.

    & New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).

  30. 30.

    Intestinal M cells. J. Biochem. 159, 151–160 (2016).

  31. 31.

    & Peyer's patches: organizing B-cell responses at the intestinal frontier. Immunol. Rev. 271, 230–245 (2016).

  32. 32.

    , & Developing lymph nodes collect CD4+CD3 LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).

  33. 33.

    & The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

  34. 34.

    et al. Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis. J. Exp. Med. 193, 621–630 (2001).

  35. 35.

    et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).

  36. 36.

    et al. NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep. 10, 2043–2054 (2015).

  37. 37.

    et al. Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl. Acad. Sci. USA 97, 10132–10137 (2000).

  38. 38.

    et al. An essential function for the nuclear receptor RORγ(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2004).

  39. 39.

    et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

  40. 40.

    et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

  41. 41.

    et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10, 1193–1199 (2009).

  42. 42.

    & Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro. Dev. Biol. 320, 185–198 (2008).

  43. 43.

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

  44. 44.

    et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

  45. 45.

    et al. Single-cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 17, 329–340 (2015).

  46. 46.

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

  47. 47.

    The evolution of cell types in animals: emerging principles from molecular studies. Nat. Rev. Genet. 9, 868–882 (2008).

  48. 48.

    , , , & Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994).

  49. 49.

    et al. RET/GFRα signals are dispensable for thymic T cell development in vivo. PLoS One 7, e52949 (2012).

  50. 50.

    et al. The neurotrophic factor receptor RET regulates IL-10 production by in vitro polarised T helper 2 cells. Eur. J. Immunol. 44, 3605–3613 (2014).

  51. 51.

    et al. The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514, 98–101 (2014).This work shows that RET drives HSC survival, which indicates that neurons and hematopoietic stem cells share survival commonalities.

  52. 52.

    & The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002).

  53. 53.

    RET revisited: expanding the oncogenic portfolio. Nat. Rev. Cancer 14, 173–186 (2014).

  54. 54.

    et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).This work demonstrates that ILC3s sense their environment and control gut defense as part of a glial–ILC3–epithelial cell unit orchestrated by neurotrophic factors.

  55. 55.

    & Ret isoform function and marker gene expression in the enteric nervous system is conserved across diverse vertebrate species. Mech. Dev. 125, 687–699 (2008).

  56. 56.

    et al. Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. Development 126, 2785–2797 (1999).

  57. 57.

    & Neural precursor death is central to the pathogenesis of intestinal aganglionosis in Ret hypomorphic mice. J. Neurosci. 30, 5211–5218 (2010).By genetic approaches, this study demonstrates that RET survival signals are the main drivers of ENS formation. Accordingly, inhibition of cell death allows the normal morphological and functional formation of ENS in RET-deficient mice.

  58. 58.

    , , , & GDNF availability determines enteric neuron number by controlling precursor proliferation. Development 130, 2187–2198 (2003).

  59. 59.

    et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).This pioneering work demonstrates that HSC mobilization is controlled by sympathetic nervous cues, via norepinephrine signals.

  60. 60.

    et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

  61. 61.

    , , & Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

  62. 62.

    et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat. Immunol. 8, 1123–1131 (2007).

  63. 63.

    & Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

  64. 64.

    , & The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

  65. 65.

    et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).

  66. 66.

    et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

  67. 67.

    et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

  68. 68.

    et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

  69. 69.

    & Feeding immunity: skepticism, delicacies and delights. Nat. Immunol. 16, 215–219 (2015).

  70. 70.

    et al. Vitamin A controls the presence of RORγ+ innate lymphoid cells and lymphoid tissue in the small intestine. J. Immunol. 196, 5148–5155 (2016).

  71. 71.

    et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

  72. 72.

    Retinoic acid production by intestinal dendritic cells and its role in T-cell trafficking. Semin. Immunol. 21, 8–13 (2009).

  73. 73.

    , & Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity 43, 107–119 (2015).

  74. 74.

    et al. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha. Immunity 34, 435–447 (2011).

  75. 75.

    et al. Retinoic acid can directly promote TGF-β-mediated Foxp3+ Treg cell conversion of naive T cells. Immunity 30, 471–472, author reply 472–473 (2009).

  76. 76.

    & Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells. Semin. Immunol. 21, 28–35 (2009).

  77. 77.

    et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

  78. 78.

    et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

  79. 79.

    et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

  80. 80.

    et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl. Acad. Sci. USA 111, 5307–5312 (2014).

  81. 81.

    , , , & 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29, 9683–9699 (2009).This study demonstrates that in addition to the fetal period of enteric neural development, adult enteric neurogenesis is critical for ENS growth and maintenance via 5-HT receptors.

  82. 82.

    et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398–3411 (2011).

  83. 83.

    , , & Development of colonic motility in the neonatal mouse-studies using spatiotemporal maps. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G930–G938 (2007).

  84. 84.

    & Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system. J. Clin. Invest. 125, 956–964 (2015).

  85. 85.

    , & Time of origin of neurons in the murine enteric nervous system: sequence in relation to phenotype. J. Comp. Neurol. 314, 789–798 (1991).

  86. 86.

    , , , & Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol. Motil. 26, 98–107 (2014).

  87. 87.

    & Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36, 305–312 (2013).

  88. 88.

    , , , & The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol. Motil. 25, 183–e88 (2013).

  89. 89.

    , , , & Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology 143, 1006–1016 (2012).

  90. 90.

    et al. Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia. J. Histochem. Cytochem. 57, 1013–1023 (2009).

  91. 91.

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

  92. 92.

    et al. Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system. Gastroenterology 145, 1323–1333 (2013).This study demonstrates that enteric neurons and glial cells express TLR2 and that the absence of TLR2 signaling results in deficits in the ENS architecture, neurochemical profile and propensity to inflammation.

  93. 93.

    et al. Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells. Mol. Cell. Neurosci. 68, 24–35 (2015).

  94. 94.

    et al. Activation of smooth muscle and myenteric plexus cells of jejunum via Toll-like receptor 4. J. Cell. Physiol. 208, 47–54 (2006).

  95. 95.

    & Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

  96. 96.

    et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).This work demonstrates that macrophages in the muscularis externa regulate peristaltic activity of the colon via BMP2 in a microbiota-dependent manner.

  97. 97.

    et al. Neuroimmune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).This study identifies macrophage-neuron interactions in the myenteric plexus that induce rapid tissue-protective responses to luminal perturbations.

  98. 98.

    & Functions and imaging of mast cell and neural axis of the gut. Gastroenterology 144, 698–704 (2013).

  99. 99.

    et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011).This study demonstrates that action potentials originating in the vagus nerve regulate T cells in the spleen, which in turn produce the acetylcholine needed to control innate immune responses.

  100. 100.

    et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).This study shows that the nicotinic acetylcholine receptor is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway, notably via inhibition of macrophage release of tumor-necrosis factor.

  101. 101.

    et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6, 844–851 (2005).

  102. 102.

    , , , & Relevance of mast cell-nerve interactions in intestinal nociception. Biochim. Biophys. Acta 1822, 74–84 (2012).

  103. 103.

    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).

  104. 104.

    , , , & Mast cells are closely apposed to nerves in the human gastrointestinal mucosa. Gastroenterology 97, 575–585 (1989).

  105. 105.

    et al. 3-D imaging, illustration, and quantitation of enteric glial network in transparent human colon mucosa. Neurogastroenterol. Motil. 25, e324–e338 (2013).

  106. 106.

    et al. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 90–100 (2013).

  107. 107.

    , & The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2011).

  108. 108.

    Emerging roles for enteric glia in gastrointestinal disorders. J. Clin. Invest. 125, 918–925 (2015).

  109. 109.

    et al. Increased mucosal nitric oxide production in ulcerative colitis is mediated in part by the enteroglial-derived S100B protein. Neurogastroenterol. Motil. 21, 1209–e112 (2009).

  110. 110.

    et al. Proinflammatory stimuli activates human-derived enteroglial cells and induces autocrine nitric oxide production. Neurogastroenterol. Motil. 23, e372–e382 (2011).

  111. 111.

    et al. Enteric glial-derived S100B protein stimulates nitric oxide production in celiac disease. Gastroenterology 133, 918–925 (2007).

  112. 112.

    et al. The protective effect of enteric glial cells on intestinal epithelial barrier function is enhanced by inhibiting inducible nitric oxide synthase activity under lipopolysaccharide stimulation. Mol. Cell. Neurosci. 46, 527–534 (2011).

  113. 113.

    et al. Major histocompatibility class II expression on the small intestinal nervous system in Crohn's disease. Gastroenterology 103, 439–447 (1992).

  114. 114.

    , , & Sequential induction of MHC antigens on autochthonous cells of ileum affected by Crohn's disease. Am. J. Pathol. 129, 493–502 (1987).

  115. 115.

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

  116. 116.

    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).

  117. 117.

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

  118. 118.

    et al. The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells. Immunity 41, 776–788 (2014).

  119. 119.

    et al. Complementarity and redundancy of IL-22-producing innate lymphoid cells. Nat. Immunol. 17, 179–186 (2016).

  120. 120.

    et al. Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349, 606–613 (2015).

  121. 121.

    et al. Evidence of innate lymphoid cell redundancy in humans. Nat. Immunol. 17, 1291–1299 (2016).

  122. 122.

    et al. Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals. J. Infect. Dis. 210, 630–640 (2014).

  123. 123.

    et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).

  124. 124.

    et al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63, 27–39 (2009).

  125. 125.

    et al. Two-photon optogenetic toolbox for fast inhibition, excitation and bistable modulation. Nat. Methods 9, 1171–1179 (2012).

  126. 126.

    et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).This study demonstrates that the intestinal microbiota modules host serotonin, which highlights a key role for host-microbiota interactions in regulating systemic serotonin-related processes.

Download references

Acknowledgements

We thank the members of our laboratories for discussions. Supported by the European Research Council (647274 for the H.V.-F. laboratory), the European Union (H.V.-F. laboratory), the Chron's and Colitis Foundation of America (H.V.-F. laboratory), the Kenneth Rainin Foundation (H.V.-F. laboratory), Fundação para a Ciência e Tecnologia, Portugal (H.V.-F. laboratory), the Medical Research Council (V.P. laboratory), the Francis Crick Institute (V.P. laboratory) and the Biotechnology and Biological Sciences Research Council (V.P. laboratory).

Author information

Affiliations

  1. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Edifício Egas Moniz, Lisboa, Portugal.

    • Henrique Veiga-Fernandes
  2. Champalimaud Research, Champalimaud Centre for the Unknown, Lisboa, Portugal.

    • Henrique Veiga-Fernandes
  3. The Francis Crick Institute, London, UK.

    • Vassilis Pachnis

Authors

  1. Search for Henrique Veiga-Fernandes in:

  2. Search for Vassilis Pachnis in:

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Henrique Veiga-Fernandes or Vassilis Pachnis.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.3634

Further reading