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Neuronal regulation of group 2 innate lymphoid cells and type 2 inflammation
CHAPTER ONE
Neuronal regulation of group 2 innate lymphoid cells and type 2 inflammation Saya Moriyamaa,†, David Artisa,b,*
a Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States b Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, United States *Corresponding author: e-mail address: [email protected]
Contents 1. Introduction 2. Group 2 innate lymphoid cells (ILC2s) 3. Neuronal regulation of ILC2s and type 2 inflammation 3.1 Catecholamines 3.2 Nicotine/acetylcholine 3.3 Neuromedin U (NMU) 3.4 Vasoactive intestinal peptide (VIP) 3.5 Calcitonin gene-related peptide (CGRP) 4. Concluding remarks Acknowledgments References
2 2 3 3 4 5 5 6 6 7 7
Abstract Diverse infectious, inflammatory, and environmental stimuli induce type 2 inflammation in the body. Group 2 innate lymphoid cells (ILC2s) are potent producers of type 2 cytokines and play important roles in promoting type 2 inflammation. In addition to alarmins and other cytokines which are known to regulate ILC2 responses, emerging studies identified the regulation of ILC2s by the nervous system through neurotransmitter and neuropeptides. In this review, we highlight recent advances in the regulation of ILC2s and type 2 inflammation by the nervous system.
†
Current address: Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Advances in Immunology, Volume 143 ISSN 0065-2776 https://doi.org/10.1016/bs.ai.2019.08.001
#
2019 Elsevier Inc. All rights reserved.
1
2
Saya Moriyama and David Artis
1. Introduction Type 2 inflammation is a prototypical response following exposure to allergens, helminth infections, adjuvants, venoms and other environmental stimuli. Initial production and release of alarmins and cytokines including interleukin (IL)-1β and IL-33 by damaged epithelial cells induce group 2 innate lymphoid cell (ILC2) responses that can be potent sources of type 2 cytokines that create an immunologic environment to promote type 2 inflammation in tissues. In this context, naı¨ve CD4+ T cells are primed and stimulated by activated antigen-presenting cells and differentiate into type 2 helper T cells (Th2 cells) which produce type 2 cytokines. Activated B cells undergo class-switching and produce IgE and IgG1. Type 2 cytokines produced by ILC2s and Th2 cells, and IgE produced by B cells, result in further activation of granulocyte effector cells, mucus production and smooth muscle contraction which in turn lead to the expulsion or encapsulation of inflammatory stimuli. Given that a large number of people worldwide suffer from various allergic disorders or are infected with helminth parasites, understanding the pathways that regulate type 2 inflammation to enhance type 2 inflammation and confer protection to helminth infections or inhibit type 2 inflammation to ameliorate allergy remains a major challenge. In this review, we highlight recent advances in our understanding of the influences of the nervous system in regulating ILC2 responses and type 2 inflammation.
2. Group 2 innate lymphoid cells (ILC2s) Type 2 cytokines such as interleukin (IL)-4, 5, 9 and 13 are produced not only by Th2 cells but also by numerous innate immune cells. ILC2s produce type 2 cytokines and are found in various immune and non-immune tissues such as lung, intestine, adipose tissue, lymphoid tissue, skin, bone marrow, and secondary lymphoid organs (Brestoff et al., 2015; Hoyler et al., 2012; Kim et al., 2013; Mjosberg et al., 2011; Molofsky et al., 2013; Monticelli et al., 2011; Moro et al., 2010; Neill et al., 2010; Price et al., 2010). Although studies have only been conducted in human and mouse so far, ILC2s might have emerged in basal vertebrates as well based on the ILC2-related gene expression profile (Vivier, van de Pavert, Cooper, & Belz, 2016). A recent fate-mapping study showed that the generation of ILC2s started during the fetal stage and a majority of the
Neuronal regulation of group 2 innate lymphoid cells
3
population is generated from common lymphoid progenitors in the bone marrow after birth (Schneider et al., 2019). Different from adaptive lymphocytes, ILC2s lack antigen-specific receptor expression and can start producing type 2 cytokines soon after activation. ILC2s also lack most of pattern-recognition receptors but express receptors for alarmins and cytokines such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP). ILC2 function has been reported in various type 2 inflammation-inducing experimental settings such as helminth infection, allergen- or virus-induced airway inflammation, skin dermatitis, and tissue repair. Since their first report in 2010, ILC2s have been intensively studied and significant advances have been made in defining the influence of various cytokines produced by immune cells and non-immune tissue resident cells. Moreover, recent reports have clarified the regulation of ILC2s not only by cytokines but also by other bioactive molecules produced by immune and non-immune cells (Kabata, Moro, & Koyasu, 2018; Klose & Artis, 2016) including the nervous system.
3. Neuronal regulation of ILC2s and type 2 inflammation Neuronal biomolecules such as neurotransmitters and neuropeptides are produced by neurons and related cells distributed all over the body to deliver signals from the central nervous system to the periphery, from the periphery to the central nervous system, or within the intestine. A number of studies showed that those neuronal signals are delivered not only within the nervous system and effector organs, but also to the immune system through neuronal receptor expression on immune cells. Below, we provide some examples of recent progresses in understanding neuronal regulation of ILC2 responses.
3.1 Catecholamines Catecholamines are monoamine neurotransmitters which transmit signals through adrenergic receptors. Dopamine synthesis from tyrosine through dihydroxyphenylalanine is mediated by tyrosine hydroxylase, and the dopamine is further hydroxylated by dopamine beta-hydroxylase to obtain norepinephrine. Norepinephrine is further carbonated by phenylethanolamine-N-methyltransferase and becomes epinephrine. Epinephrine and norepinephrine are released by adrenal glands and adrenergic nerves following “fight-or-flight” stimuli. The receptors for
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catecholamines, adrenergic receptors, are classified into two groups which are further subdivided into subgroups (α1 and α2; β1, β2 and β3). Most adrenergic receptors are stimulatory receptors except for β2 receptor, which has an inhibitory effect depending on signal strength. β2 adrenergic receptor (β2AR) is expressed on various immune cells such as T cells, B cells and other innate cells, and recent publications revealed its role on ILC2s (Elenkov, Wilder, Chrousos, & Vizi, 2000; Moriyama et al., 2018; Muller et al., 2014; Sternberg, 2006). β2AR expression was found on ILC2s from gut-related tissues (mesenteric lymph nodes, small intestinal lamina propria and colonic lamina propria) and the lung. After infection with the type 2 inflammation-stimulating gastrointestinal helminth Nippostrongyrus brasiliensis, enhanced ILC2 responses and type 2 inflammation were observed in the intestine from β2AR-deficient mice, and conversely, ILC2 responses and type 2 inflammation were reduced following β2AR-agonist treatment. By using conditional β2AR-deficient mice (IL7R-cre Adrb2-flox mice with CD4+ cell depletion), or by transferring ILC2 progenitors from β2AR-deficient mice or wild-type mice into ILC-deficient Rag2/Il2rg double knockout mice, the group generated ILC2-specific β2AR-deficient mice and confirmed that the β2AR expressed on ILC2s negatively regulates ILC2 responses and type 2 inflammation (Moriyama et al., 2018). Mechanistically, β2AR inhibits proliferation of ILC2s in a cell-intrinsic manner during inflammation. ILC2 responses in the lung were similarly negatively regulated by β2AR in β2AR-deficient mice and agonist-treated mice. Although an ILC2-specific conditional mouse model is needed to demonstrate the direct importance of β2AR on lung ILC2s, β2AR-agonists have been widely used to treat asthma. β2AR-mediated ILC2 regulation could be one of the mechanisms of β2AR-agonists effect in asthma, in which ILC2s are involved in the pathogenesis.
3.2 Nicotine/acetylcholine Another group of neurotransmitters, acetylcholine, is produced in cholinergic nerves. Acetylcholine signals through ligand-gated ion channel nicotinic acetylcholine receptors, which also bind to a tobacco derived-alkaloid nicotine and muscarinic acetylcholine receptors, which are also sensitive to a mushroom derived-alkaloid muscarine. Lung ILC2s express one of the nicotinic acetylcholine receptors, α7 nicotinic acetylcholine receptor (α7nAChR) at steady state, and this expression is further upregulated
Neuronal regulation of group 2 innate lymphoid cells
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following alarmin-induced activation (Galle-Treger et al., 2016). Interestingly, stimulation with α7nAChR agonist suppresses type 2 cytokine production from ILC2s and ameliorates ILC2-mediated lung inflammation induced via IL-33 stimulation or Alternaria alternata inhalation. This suppressive function of α7nAChR on ILC2s may be one mechanism underlying the observed reduced pulmonary allergic inflammation induced by nicotine treatment (Mishra et al., 2008).
3.3 Neuromedin U (NMU) Neuromedin U (NMU) is a neuropeptide produced by cholinergic neurons and signals through its receptors NMUR1 and NMUR2 (Howard et al., 2000). In contrast to NMUR2 which is preferentially expressed in the central nervous system, NMUR1 expression is restricted to the periphery. Mouse studies using Nmur1-reporter mice showed its restricted expression on ILC2s (Klose et al., 2017). NMUR1 is expressed on approximately half of the ILC2s in the intestine and in the lung, and serves as a stimulatory receptor through ERK1/2 activation (Cardoso et al., 2017; Klose et al., 2017; Wallrapp et al., 2017). Interestingly, ILC2s are found in close proximity to cholinergic neurons in the intestinal submucosa. Following helminth infection and allergen inhalation, NMU is rapidly produced by cholinergic neurons and induce a cell activation/proliferation as well as type 2 cytokine production by ILC2s. Thus, NMU serves as an early stimulation factor for ILC2s in the lung and in the gut during inflammation.
3.4 Vasoactive intestinal peptide (VIP) Another neuropeptide vasoactive intestinal peptide (VIP) is found both in the central and peripheral nervous system (Delgado & Ganea, 2013). VIP is a neuropeptide expressed by neurons innervated in many organs including intestine, lung and immune organs. In addition to neurons, VIP is produced by immune cells and endocrine cells, and signals through receptors VPAC1 and VPAC2. Lung and intestinal ILC2s express VPAC1 and VPAC2 (Nussbaum et al., 2013). The activation of lung ILC2s is inhibited by VPAC2 blockade, and sensory neurons produce VIP in the lung following IL-5 stimulation, which suggests a positive feedback loop between ILC2s/type 2 inflammation/sensory neurons in the lung (Talbot et al., 2015). Intestinal ILC2s cultured with IL-7 and VIP or VPAC2-agonist produced more IL-5 compared to IL-7 alone (Nussbaum et al., 2013). Together with the coordination of circadian rhythms by VIP
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(Aton, Colwell, Harmar, Waschek, & Herzog, 2005), this increased IL-5 production by ILC2s through VIP may be linked to the variation of circulating eosinophils in the blood.
3.5 Calcitonin gene-related peptide (CGRP) Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by alternative splicing of the calcitonin gene. CGRP is released from neurons, mostly from sensory neurons, and acts as a vasodilator and a transmitter, and regulates cardiovascular diseases and migraine (Iyengar, Ossipov, & Johnson, 2017). Recent study showed that CGRP produced by rare airway epithelial cells, pulmonary neuroendocrine cells (PNECs), stimulates ILC2s in the lung (Sui et al., 2018). PNECs are found in close proximity to ILC2s in the lung, especially in the airway branch points and CGRP upregulated type 2 cytokine production from ILC2s in vitro. PNEC-deficient mice responded poorly to ovalbumin-induced asthma model and inactivation of the CGRP receptor Calcrl in ILC2s reduced lung inflammation. Intratracheal CGRP injection together with the neurotransmitter GABA restored the ovalbumin responses in vivo. Together, PNECs regulate ILC2 responses and type 2 inflammation in the lung by producing CGRP and GABA upon allergen exposure.
4. Concluding remarks The emerging studies discussed here provide new insights into neuronal regulation of ILC2 responses (summarized in Fig. 1 and Table 1). Notably, there appears to be tissue- and context-specific roles for the nervous system in selective positive and negative regulation of ILC and other immune cell responses, an area that will require further investigation. In this context, given recent reports describing shared and tissue-dependent
Fig. 1 Multiple regulatory pathways of ILC2. ILC2s receive stimulatory and inhibitory signals from various cells such as immune cells, epithelial cells and stromal cells. A growing number of studies have also shown ILC2 regulation by other cell types such as nerves and endocrine cells.
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Neuronal regulation of group 2 innate lymphoid cells
Table 1 Neural regulation pathway of ILC2. Regulation pathway Ligand and producer
Receptor
Stimulatory
NMUR1
NMU Cholinergic nerve
VIP VPAC1 and VPAC2 Nerve, immune cells, endocrine cells
Inhibitory
CGRP Sensory neuron, PNECs
Calcrl
Catecholamine Adrenergic nerve
β 2AR
α 7nAChR agonist ?
α 7nAChR
phenotypes among ILCs in different tissues (Robinette et al., 2015; Simoni et al., 2017; Yudanin et al., 2019), it would be of interest to examine whether ILCs in distinct organs are differentially regulated by the nervous system. Additionally, the potential of manipulating neuronal-derived signals in the context of inflammation is an attractive therapeutic prospect.
Acknowledgments We thank the members of the Artis lab for discussion and critical reading of the manuscript. Research in the Artis lab is supported by a JSPS Overseas Research Fellowships (to S.M.), the National Institutes of Health (AI074878, AI095466, AI095608 and AI102942), the Burroughs Wellcome Fund, the Crohn’s and Colitis Foundation, Cure for IBD and the Rosanne H. Silbermann Foundation (all to D.A.).
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Muller, P. A., Koscso, B., Rajani, G. M., Stevanovic, K., Berres, M. L., Hashimoto, D., et al. (2014). Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell, 158(5), 1210. https://doi.org/10.1016/j.cell.2014.08.002. Neill, D. R., Wong, S. H., Bellosi, A., Flynn, R. J., Daly, M., Langford, T. K., et al. (2010). Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature, 464(7293), 1367–1370. https://doi.org/10.1038/nature08900. Nussbaum, J. C., Van Dyken, S. J., von Moltke, J., Cheng, L. E., Mohapatra, A., Molofsky, A. B., et al. (2013). Type 2 innate lymphoid cells control eosinophil homeostasis. Nature, 502(7470), 245–248. https://doi.org/10.1038/nature12526. Price, A. E., Liang, H. E., Sullivan, B. M., Reinhardt, R. L., Eisley, C. J., Erle, D. J., et al. (2010). Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proceedings of the National Academy of Sciences of the United States of America, 107(25), 11489–11494. https://doi.org/10.1073/pnas.1003988107. Robinette, M. L., Fuchs, A., Cortez, V. S., Lee, J. S., Wang, Y., Durum, S. K., et al. (2015). Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nature Immunology, 16(3), 306–317. https://doi.org/10.1038/ni.3094. Schneider, C., Lee, J., Koga, S., Ricardo-Gonzalez, R. R., Nussbaum, J. C., Smith, L. K., et al. (2019). Tissue-resident group 2 innate lymphoid cells differentiate by layered ontogeny and in situ perinatal priming. Immunity, 50, 1425–1438.e5. https://doi.org/ 10.1016/j.immuni.2019.04.019. Simoni, Y., Fehlings, M., Kloverpris, H. N., McGovern, N., Koo, S. L., Loh, C. Y., et al. (2017). Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity, 46(1), 148–161. https://doi.org/10.1016/ j.immuni.2016.11.005. Sternberg, E. M. (2006). Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nature Reviews. Immunology, 6(4), 318–328. https://doi.org/ 10.1038/nri1810. Sui, P., Wiesner, D. L., Xu, J., Zhang, Y., Lee, J., Van Dyken, S., et al. (2018). Pulmonary neuroendocrine cells amplify allergic asthma responses. Science, 360(6393), eaan8546. https://doi.org/10.1126/science.aan8546. Talbot, S., Abdulnour, R. E., Burkett, P. R., Lee, S., Cronin, S. J., Pascal, M. A., et al. (2015). Silencing nociceptor neurons reduces allergic airway inflammation. Neuron, 87(2), 341–354. https://doi.org/10.1016/j.neuron.2015.06.007. Vivier, E., van de Pavert, S. A., Cooper, M. D., & Belz, G. T. (2016). The evolution of innate lymphoid cells. Nature Immunology, 17(7), 790–794. https://doi.org/10.1038/ ni.3459. Wallrapp, A., Riesenfeld, S. J., Burkett, P. R., Abdulnour, R. E., Nyman, J., Dionne, D., et al. (2017). The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature, 549(7672), 351–356. https://doi.org/10.1038/nature24029. Yudanin, N. A., Schmitz, F., Flamar, A. L., Thome, J. J. C., Tait Wojno, E., Moeller, J. B., et al. (2019). Spatial and temporal mapping of human innate lymphoid cells reveals elements of tissue specificity. Immunity, 50(2), 505–519 e504. https://doi.org/ 10.1016/j.immuni.2019.01.012.
Neuronal regulation of group 2 innate lymphoid cells and type 2 inflammation Saya Moriyamaa,†, David Artisa,b,*
a Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States b Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, United States *Corresponding author: e-mail address: [email protected]
Contents 1. Introduction 2. Group 2 innate lymphoid cells (ILC2s) 3. Neuronal regulation of ILC2s and type 2 inflammation 3.1 Catecholamines 3.2 Nicotine/acetylcholine 3.3 Neuromedin U (NMU) 3.4 Vasoactive intestinal peptide (VIP) 3.5 Calcitonin gene-related peptide (CGRP) 4. Concluding remarks Acknowledgments References
2 2 3 3 4 5 5 6 6 7 7
Abstract Diverse infectious, inflammatory, and environmental stimuli induce type 2 inflammation in the body. Group 2 innate lymphoid cells (ILC2s) are potent producers of type 2 cytokines and play important roles in promoting type 2 inflammation. In addition to alarmins and other cytokines which are known to regulate ILC2 responses, emerging studies identified the regulation of ILC2s by the nervous system through neurotransmitter and neuropeptides. In this review, we highlight recent advances in the regulation of ILC2s and type 2 inflammation by the nervous system.
†
Current address: Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Advances in Immunology, Volume 143 ISSN 0065-2776 https://doi.org/10.1016/bs.ai.2019.08.001
#
2019 Elsevier Inc. All rights reserved.
1
2
Saya Moriyama and David Artis
1. Introduction Type 2 inflammation is a prototypical response following exposure to allergens, helminth infections, adjuvants, venoms and other environmental stimuli. Initial production and release of alarmins and cytokines including interleukin (IL)-1β and IL-33 by damaged epithelial cells induce group 2 innate lymphoid cell (ILC2) responses that can be potent sources of type 2 cytokines that create an immunologic environment to promote type 2 inflammation in tissues. In this context, naı¨ve CD4+ T cells are primed and stimulated by activated antigen-presenting cells and differentiate into type 2 helper T cells (Th2 cells) which produce type 2 cytokines. Activated B cells undergo class-switching and produce IgE and IgG1. Type 2 cytokines produced by ILC2s and Th2 cells, and IgE produced by B cells, result in further activation of granulocyte effector cells, mucus production and smooth muscle contraction which in turn lead to the expulsion or encapsulation of inflammatory stimuli. Given that a large number of people worldwide suffer from various allergic disorders or are infected with helminth parasites, understanding the pathways that regulate type 2 inflammation to enhance type 2 inflammation and confer protection to helminth infections or inhibit type 2 inflammation to ameliorate allergy remains a major challenge. In this review, we highlight recent advances in our understanding of the influences of the nervous system in regulating ILC2 responses and type 2 inflammation.
2. Group 2 innate lymphoid cells (ILC2s) Type 2 cytokines such as interleukin (IL)-4, 5, 9 and 13 are produced not only by Th2 cells but also by numerous innate immune cells. ILC2s produce type 2 cytokines and are found in various immune and non-immune tissues such as lung, intestine, adipose tissue, lymphoid tissue, skin, bone marrow, and secondary lymphoid organs (Brestoff et al., 2015; Hoyler et al., 2012; Kim et al., 2013; Mjosberg et al., 2011; Molofsky et al., 2013; Monticelli et al., 2011; Moro et al., 2010; Neill et al., 2010; Price et al., 2010). Although studies have only been conducted in human and mouse so far, ILC2s might have emerged in basal vertebrates as well based on the ILC2-related gene expression profile (Vivier, van de Pavert, Cooper, & Belz, 2016). A recent fate-mapping study showed that the generation of ILC2s started during the fetal stage and a majority of the
Neuronal regulation of group 2 innate lymphoid cells
3
population is generated from common lymphoid progenitors in the bone marrow after birth (Schneider et al., 2019). Different from adaptive lymphocytes, ILC2s lack antigen-specific receptor expression and can start producing type 2 cytokines soon after activation. ILC2s also lack most of pattern-recognition receptors but express receptors for alarmins and cytokines such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP). ILC2 function has been reported in various type 2 inflammation-inducing experimental settings such as helminth infection, allergen- or virus-induced airway inflammation, skin dermatitis, and tissue repair. Since their first report in 2010, ILC2s have been intensively studied and significant advances have been made in defining the influence of various cytokines produced by immune cells and non-immune tissue resident cells. Moreover, recent reports have clarified the regulation of ILC2s not only by cytokines but also by other bioactive molecules produced by immune and non-immune cells (Kabata, Moro, & Koyasu, 2018; Klose & Artis, 2016) including the nervous system.
3. Neuronal regulation of ILC2s and type 2 inflammation Neuronal biomolecules such as neurotransmitters and neuropeptides are produced by neurons and related cells distributed all over the body to deliver signals from the central nervous system to the periphery, from the periphery to the central nervous system, or within the intestine. A number of studies showed that those neuronal signals are delivered not only within the nervous system and effector organs, but also to the immune system through neuronal receptor expression on immune cells. Below, we provide some examples of recent progresses in understanding neuronal regulation of ILC2 responses.
3.1 Catecholamines Catecholamines are monoamine neurotransmitters which transmit signals through adrenergic receptors. Dopamine synthesis from tyrosine through dihydroxyphenylalanine is mediated by tyrosine hydroxylase, and the dopamine is further hydroxylated by dopamine beta-hydroxylase to obtain norepinephrine. Norepinephrine is further carbonated by phenylethanolamine-N-methyltransferase and becomes epinephrine. Epinephrine and norepinephrine are released by adrenal glands and adrenergic nerves following “fight-or-flight” stimuli. The receptors for
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catecholamines, adrenergic receptors, are classified into two groups which are further subdivided into subgroups (α1 and α2; β1, β2 and β3). Most adrenergic receptors are stimulatory receptors except for β2 receptor, which has an inhibitory effect depending on signal strength. β2 adrenergic receptor (β2AR) is expressed on various immune cells such as T cells, B cells and other innate cells, and recent publications revealed its role on ILC2s (Elenkov, Wilder, Chrousos, & Vizi, 2000; Moriyama et al., 2018; Muller et al., 2014; Sternberg, 2006). β2AR expression was found on ILC2s from gut-related tissues (mesenteric lymph nodes, small intestinal lamina propria and colonic lamina propria) and the lung. After infection with the type 2 inflammation-stimulating gastrointestinal helminth Nippostrongyrus brasiliensis, enhanced ILC2 responses and type 2 inflammation were observed in the intestine from β2AR-deficient mice, and conversely, ILC2 responses and type 2 inflammation were reduced following β2AR-agonist treatment. By using conditional β2AR-deficient mice (IL7R-cre Adrb2-flox mice with CD4+ cell depletion), or by transferring ILC2 progenitors from β2AR-deficient mice or wild-type mice into ILC-deficient Rag2/Il2rg double knockout mice, the group generated ILC2-specific β2AR-deficient mice and confirmed that the β2AR expressed on ILC2s negatively regulates ILC2 responses and type 2 inflammation (Moriyama et al., 2018). Mechanistically, β2AR inhibits proliferation of ILC2s in a cell-intrinsic manner during inflammation. ILC2 responses in the lung were similarly negatively regulated by β2AR in β2AR-deficient mice and agonist-treated mice. Although an ILC2-specific conditional mouse model is needed to demonstrate the direct importance of β2AR on lung ILC2s, β2AR-agonists have been widely used to treat asthma. β2AR-mediated ILC2 regulation could be one of the mechanisms of β2AR-agonists effect in asthma, in which ILC2s are involved in the pathogenesis.
3.2 Nicotine/acetylcholine Another group of neurotransmitters, acetylcholine, is produced in cholinergic nerves. Acetylcholine signals through ligand-gated ion channel nicotinic acetylcholine receptors, which also bind to a tobacco derived-alkaloid nicotine and muscarinic acetylcholine receptors, which are also sensitive to a mushroom derived-alkaloid muscarine. Lung ILC2s express one of the nicotinic acetylcholine receptors, α7 nicotinic acetylcholine receptor (α7nAChR) at steady state, and this expression is further upregulated
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following alarmin-induced activation (Galle-Treger et al., 2016). Interestingly, stimulation with α7nAChR agonist suppresses type 2 cytokine production from ILC2s and ameliorates ILC2-mediated lung inflammation induced via IL-33 stimulation or Alternaria alternata inhalation. This suppressive function of α7nAChR on ILC2s may be one mechanism underlying the observed reduced pulmonary allergic inflammation induced by nicotine treatment (Mishra et al., 2008).
3.3 Neuromedin U (NMU) Neuromedin U (NMU) is a neuropeptide produced by cholinergic neurons and signals through its receptors NMUR1 and NMUR2 (Howard et al., 2000). In contrast to NMUR2 which is preferentially expressed in the central nervous system, NMUR1 expression is restricted to the periphery. Mouse studies using Nmur1-reporter mice showed its restricted expression on ILC2s (Klose et al., 2017). NMUR1 is expressed on approximately half of the ILC2s in the intestine and in the lung, and serves as a stimulatory receptor through ERK1/2 activation (Cardoso et al., 2017; Klose et al., 2017; Wallrapp et al., 2017). Interestingly, ILC2s are found in close proximity to cholinergic neurons in the intestinal submucosa. Following helminth infection and allergen inhalation, NMU is rapidly produced by cholinergic neurons and induce a cell activation/proliferation as well as type 2 cytokine production by ILC2s. Thus, NMU serves as an early stimulation factor for ILC2s in the lung and in the gut during inflammation.
3.4 Vasoactive intestinal peptide (VIP) Another neuropeptide vasoactive intestinal peptide (VIP) is found both in the central and peripheral nervous system (Delgado & Ganea, 2013). VIP is a neuropeptide expressed by neurons innervated in many organs including intestine, lung and immune organs. In addition to neurons, VIP is produced by immune cells and endocrine cells, and signals through receptors VPAC1 and VPAC2. Lung and intestinal ILC2s express VPAC1 and VPAC2 (Nussbaum et al., 2013). The activation of lung ILC2s is inhibited by VPAC2 blockade, and sensory neurons produce VIP in the lung following IL-5 stimulation, which suggests a positive feedback loop between ILC2s/type 2 inflammation/sensory neurons in the lung (Talbot et al., 2015). Intestinal ILC2s cultured with IL-7 and VIP or VPAC2-agonist produced more IL-5 compared to IL-7 alone (Nussbaum et al., 2013). Together with the coordination of circadian rhythms by VIP
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(Aton, Colwell, Harmar, Waschek, & Herzog, 2005), this increased IL-5 production by ILC2s through VIP may be linked to the variation of circulating eosinophils in the blood.
3.5 Calcitonin gene-related peptide (CGRP) Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by alternative splicing of the calcitonin gene. CGRP is released from neurons, mostly from sensory neurons, and acts as a vasodilator and a transmitter, and regulates cardiovascular diseases and migraine (Iyengar, Ossipov, & Johnson, 2017). Recent study showed that CGRP produced by rare airway epithelial cells, pulmonary neuroendocrine cells (PNECs), stimulates ILC2s in the lung (Sui et al., 2018). PNECs are found in close proximity to ILC2s in the lung, especially in the airway branch points and CGRP upregulated type 2 cytokine production from ILC2s in vitro. PNEC-deficient mice responded poorly to ovalbumin-induced asthma model and inactivation of the CGRP receptor Calcrl in ILC2s reduced lung inflammation. Intratracheal CGRP injection together with the neurotransmitter GABA restored the ovalbumin responses in vivo. Together, PNECs regulate ILC2 responses and type 2 inflammation in the lung by producing CGRP and GABA upon allergen exposure.
4. Concluding remarks The emerging studies discussed here provide new insights into neuronal regulation of ILC2 responses (summarized in Fig. 1 and Table 1). Notably, there appears to be tissue- and context-specific roles for the nervous system in selective positive and negative regulation of ILC and other immune cell responses, an area that will require further investigation. In this context, given recent reports describing shared and tissue-dependent
Fig. 1 Multiple regulatory pathways of ILC2. ILC2s receive stimulatory and inhibitory signals from various cells such as immune cells, epithelial cells and stromal cells. A growing number of studies have also shown ILC2 regulation by other cell types such as nerves and endocrine cells.
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Neuronal regulation of group 2 innate lymphoid cells
Table 1 Neural regulation pathway of ILC2. Regulation pathway Ligand and producer
Receptor
Stimulatory
NMUR1
NMU Cholinergic nerve
VIP VPAC1 and VPAC2 Nerve, immune cells, endocrine cells
Inhibitory
CGRP Sensory neuron, PNECs
Calcrl
Catecholamine Adrenergic nerve
β 2AR
α 7nAChR agonist ?
α 7nAChR
phenotypes among ILCs in different tissues (Robinette et al., 2015; Simoni et al., 2017; Yudanin et al., 2019), it would be of interest to examine whether ILCs in distinct organs are differentially regulated by the nervous system. Additionally, the potential of manipulating neuronal-derived signals in the context of inflammation is an attractive therapeutic prospect.
Acknowledgments We thank the members of the Artis lab for discussion and critical reading of the manuscript. Research in the Artis lab is supported by a JSPS Overseas Research Fellowships (to S.M.), the National Institutes of Health (AI074878, AI095466, AI095608 and AI102942), the Burroughs Wellcome Fund, the Crohn’s and Colitis Foundation, Cure for IBD and the Rosanne H. Silbermann Foundation (all to D.A.).
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