Neuro-immune Interactions in the Tissues

The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease. The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease. The immune system is composed of a diverse array of immune cells including innate and adaptive lymphocytes and myeloid cells. This system can directly sense internal and environmental stimuli, and it participates in a wide variety of physiological processes in tissues, including host defense against pathogens, interactions with the microbiota at barrier surfaces, and maintenance of tissue homeostasis (Belkaid and Hand, 2014Belkaid Y. Hand T.W. Role of the microbiota in immunity and inflammation.Cell. 2014; 157: 121-141Abstract Full Text Full Text PDF PubMed Scopus (1815) Google Scholar, Rankin and Artis, 2018Rankin L.C. Artis D. Beyond Host Defense: Emerging Functions of the Immune System in Regulating Complex Tissue Physiology.Cell. 2018; 173: 554-567Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). However, excessive immune responses can lead to chronic inflammation and autoimmune diseases (Pahwa et al., 2020Pahwa R. Goyal A. Bansal P. Jialal I. Chronic Inflammation.StatPearls. 2020; https://www.ncbi.nlm.nih.gov/books/NBK493173/Google Scholar, Rose and Mackay, 2019Rose N.R. Mackay I.R. The autoimmune diseases. Academic Press, 2019Google Scholar). Tissues and organs are also densely innervated by distinct branches of the nervous system that, like the immune system, directly sense and respond rapidly to environmental cues. The immune and nervous systems interact at various levels during embryonic development, in homeostasis, and in disease. For example, neurotransmitters and neuropeptides can directly impact immune cell function, including the regulation of immune responses to pathogens and tissue damage (Baral et al., 2019Baral P. Udit S. Chiu I.M. Pain and immunity: implications for host defence.Nat. Rev. Immunol. 2019; 19: 433-447Crossref PubMed Scopus (72) Google Scholar, Godinho-Silva et al., 2019aGodinho-Silva C. Cardoso F. Veiga-Fernandes H. Neuro-Immune Cell Units: A New Paradigm in Physiology.Annu. Rev. Immunol. 2019; 37: 19-46Crossref PubMed Scopus (58) Google Scholar, Huh and Veiga-Fernandes, 2019Huh J.R. Veiga-Fernandes H. Neuroimmune circuits in inter-organ communication.Nat. Rev. Immunol. 2019; https://doi.org/10.1038/s41577-019-0247-zCrossref PubMed Scopus (30) Google Scholar, Klose and Artis, 2019Klose C.S. Artis D. Neuronal regulation of innate lymphoid cells.Curr. Opin. Immunol. 2019; 56: 94-99Crossref PubMed Scopus (20) Google Scholar, Veiga-Fernandes and Mucida, 2016Veiga-Fernandes H. Mucida D. Neuro-Immune Interactions at Barrier Surfaces.Cell. 2016; 165: 801-811Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). How neuro-immune interactions are established and maintained in different tissues and the specific cellular interactions that underlie immune and homeostatic responses therein are important areas of investigation. Recent technological developments, including novel transgenic mouse strains and in vivo neuronal ablation or activation techniques like optogenetics and chemogenetics, are enabling a deeper examination of the cellular and molecular mechanisms that underlie neuro-immune interactions in the context of health and disease. Here, we critically review recent advances in the understanding of neuronal regulation of host defense, inflammation, and homeostasis in peripheral tissues. We argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity and contexts of pathology and develop improved approaches to treat pain and disease. The nervous system is organized as the central nervous system (CNS), composed of the brain and spinal cord, and the peripheral nervous system (PNS). The PNS is divided into the somatosensory and autonomic systems. Every division of the PNS is able to communicate with immune cells, and immune cells express receptors for many classes of neurotransmitters, including catecholamines, gamma-aminobutyric acid (GABA), acetylcholine, and neuropeptides (e.g., calcitonin gene-related peptide [CGRP], substance P [SP], vasoactive intestinal peptide [VIP], and neuromedin U [NMU]) (Godinho-Silva et al., 2019aGodinho-Silva C. Cardoso F. Veiga-Fernandes H. Neuro-Immune Cell Units: A New Paradigm in Physiology.Annu. Rev. Immunol. 2019; 37: 19-46Crossref PubMed Scopus (58) Google Scholar). The somatosensory nervous system detects environmental and internal stimuli. The cell bodies of somatosensory neurons reside within the dorsal root ganglia (DRG) and trigeminal ganglia (TG), mediating touch, thermoception, proprioception, itch, and pain. Nociceptors are specialized somatosensory neurons that respond to noxious and/or injurious stimuli including intense heat, mechanical injury, and inflammatory mediators (Abraira and Ginty, 2013Abraira V.E. Ginty D.D. The sensory neurons of touch.Neuron. 2013; 79: 618-639Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar, Basbaum et al., 2009Basbaum A.I. Bautista D.M. Scherrer G. Julius D. Cellular and molecular mechanisms of pain.Cell. 2009; 139: 267-284Abstract Full Text Full Text PDF PubMed Scopus (2074) Google Scholar). Because nociceptors contain dense-core vesicles storing neuropeptides not only in their synaptic terminals at the CNS but also in their nerve endings within the peripheral tissues, they are simultaneously equipped to inform the CNS about the presence of a noxious stimulus and to modulate immune cell responses at the tissue that is receiving the stimulus. The autonomic system consists of the parasympathetic, sympathetic, and enteric nervous systems. Parasympathetic neurons mainly exit the brain through the vagus nerve, sending efferent signals to visceral organs including the heart, lungs, and intestine via the neurotransmitter acetylcholine (ACh). The vagus nerve is bi-directional and also carries sensory information from visceral organs to the CNS via the nodose and jugular ganglia (Chang et al., 2015Chang R.B. Strochlic D.E. Williams E.K. Umans B.D. Liberles S.D. Vagal Sensory Neuron Subtypes that Differentially Control Breathing.Cell. 2015; 161: 622-633Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, Umans and Liberles, 2018Umans B.D. Liberles S.D. Neural Sensing of Organ Volume.Trends Neurosci. 2018; 41: 911-924Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, Williams et al., 2016Williams E.K. Chang R.B. Strochlic D.E. Umans B.D. Lowell B.B. Liberles S.D. Sensory Neurons that Detect Stretch and Nutrients in the Digestive System.Cell. 2016; 166: 209-221Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). Vagal afferent sensing of intestinal contents and activation of vagal efferent neurons that signal back to the intestine are key components of the “gut-brain axis.” Sympathetic neurons mediate the body’s “fight or flight” response. Preganglionic sympathetic neurons in the spinal cord project fibers to peripheral ganglia, where post-ganglionic neurons send efferent signals to the tissues via catecholamines (dopamine, norepinephrine, and epinephrine). The intrinsic enteric nervous system (ENS) is fully contained within the intestine, composed of sensory neurons that detect intestinal contents and motor neurons that drive secretory function and peristalsis (Furness, 2012Furness J.B. The enteric nervous system and neurogastroenterology.Nat. Rev. Gastroenterol. Hepatol. 2012; 9: 286-294Crossref PubMed Scopus (669) Google Scholar, Furness, 2016Furness J.B. Integrated Neural and Endocrine Control of Gastrointestinal Function.Adv. Exp. Med. Biol. 2016; 891: 159-173Crossref PubMed Scopus (35) Google Scholar). Enteric neurons are housed within the myenteric plexus (within the intestinal wall) or the submucosal plexus (beneath the lamina propria). Whereas both neurons and immune cells can sense environmental stimuli, neuronal control of immunity, via the integrated nature of the neuronal response, enables increased reaction speed and physiological reach. Reaction to the stimuli and transmission of the signal perform on a timescale of milliseconds in neurons, rather than minutes to hours in the immune system, highlighting the selective advantage of co-evolved immune and neuronal systems (see Box 1). The impact of neuro-immune interactions also appears to be evolutionarily conserved. For example, C. elegans has evolved mechanisms by which neurons mediate both behavioral immunity and neuro-immune molecular signaling to protect against pathogens (Singh and Aballay, 2019Singh J. Aballay A. Neural control of behavioral and molecular defenses in C. elegans.Curr. Opin. Neurobiol. 2019; 62: 34-40Crossref PubMed Scopus (7) Google Scholar, Wani et al., 2019Wani K.A. Goswamy D. Irazoqui J.E. Nervous system control of intestinal host defense in C. elegans.Curr. Opin. Neurobiol. 2019; 62: 1-9Crossref PubMed Scopus (8) Google Scholar). In mammals, the sensory and autonomic systems are coordinated through neural reflex circuits that rapidly respond to changes and regulate immunity. A major neural circuit that modulates immune responses was discovered and coined the cholinergic “anti-inflammatory reflex” by Tracey and colleagues (Pavlov et al., 2018Pavlov V.A. Chavan S.S. Tracey K.J. Molecular and Functional Neuroscience in Immunity.Annu. Rev. Immunol. 2018; 36: 783-812Crossref PubMed Scopus (121) Google Scholar, Tracey, 2002Tracey K.J. The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2299) Google Scholar). In this reflex, peripheral inflammation is sensed by vagal sensory afferent neurons, activating a brainstem circuit that leads to decreased peripheral cytokine production via vagal efferent neuron signaling. At a tissue level, nociceptor neurons utilize local axonal reflexes—reflexes in a single neuron, from one afferent nerve ending to an axon bifurcation and propagated to another nerve ending—to rapidly respond to danger and release neuropeptides that signal to the vasculature and to immune cells (Baral et al., 2019Baral P. Udit S. Chiu I.M. Pain and immunity: implications for host defence.Nat. Rev. Immunol. 2019; 19: 433-447Crossref PubMed Scopus (72) Google Scholar, Pinho-Ribeiro et al., 2017Pinho-Ribeiro F.A. Verri Jr., W.A. Chiu I.M. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation.Trends Immunol. 2017; 38: 5-19Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar). Thus, the PNS can integrate responses to challenges at a tissue and systemic level and can coordinate with immune responses accordingly.Box 1Neural Regulation of Immunity in Non-mammalian OrganismsThe evidence for communication between the nervous and immune systems extends to non-mammalian organisms, including the roundworm, C. elegans. As they feed on bacteria, C. elegans must quickly distinguish between pathogenic and beneficial microbes. In these worms, the sensory nervous system plays a key role in directly detecting bacterial pathogens and mediating avoidance behavior (Meisel et al., 2014Meisel J.D. Panda O. Mahanti P. Schroeder F.C. Kim D.H. Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans.Cell. 2014; 159: 267-280Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Zhang et al., 2005Zhang Y. Lu H. Bargmann C.I. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans.Nature. 2005; 438: 179-184Crossref PubMed Scopus (473) Google Scholar). Neurons also regulate immune responses at the cellular and molecular level in C. elegans. Specific sensory neuron subtypes expressing the GPCRs octopamine receptor-1 (OCTR-1) or neuropeptide receptor resemblance-1 (NPR-1) regulate immune defenses in C. elegans through modulation of innate immune signaling, microbial killing pathways, and the unfolded protein response (Styer et al., 2008Styer K.L. Singh V. Macosko E. Steele S.E. Bargmann C.I. Aballay A. Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR.Science. 2008; 322: 460-464Crossref PubMed Scopus (155) Google Scholar, Sun et al., 2011Sun J. Singh V. Kajino-Sakamoto R. Aballay A. Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes.Science. 2011; 332: 729-732Crossref PubMed Scopus (153) Google Scholar). Neuro-endocrine signaling through an insulin-like neuropeptide INS7 also regulates clearance of bacterial infection (Kawli and Tan, 2008Kawli T. Tan M.W. Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling.Nat. Immunol. 2008; 9: 1415-1424Crossref PubMed Scopus (80) Google Scholar). In the skin, neuronal expression of a TGFβ homolog in C. elegans promotes antimicrobial peptide expression during fungal pathogen exposure (Zugasti and Ewbank, 2009Zugasti O. Ewbank J.J. Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-beta signaling pathway in Caenorhabditis elegans epidermis.Nat. Immunol. 2009; 10: 249-256Crossref PubMed Scopus (122) Google Scholar). In the intestine of C. elegans, neural signaling through acetylcholine induces Wnt pathway genes that upregulate antimicrobial C-type lectins and lysozymes during bacterial infection (Labed et al., 2018Labed S.A. Wani K.A. Jagadeesan S. Hakkim A. Najibi M. Irazoqui J.E. ). Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection.Immunity. 2018; 48: 963-978.e963Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). In Drosophila, sensory neuron signaling through Activin-β (a TGF-β family ligand) regulates proliferation and adhesion of hemocytes (Makhijani et al., 2017Makhijani K. Alexander B. Rao D. Petraki S. Herboso L. Kukar K. Batool I. Wachner S. Gold K.S. Wong C. et al.Regulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons.Nat. Commun. 2017; 8: 15990Crossref PubMed Scopus (27) Google Scholar). In zebrafish, olfactory sensory neurons rapidly regulate CD8+ T cell responses during rhabdovirus infections in a tropomyosin receptor kinase A (TrkA)-dependent manner (Sepahi et al., 2019Sepahi A. Kraus A. Casadei E. Johnston C.A. Galindo-Villegas J. Kelly C. García-Moreno D. Muñoz P. Mulero V. Huertas M. Salinas I. Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner.Proc. Natl. Acad. Sci. USA. 2019; 116: 12428-12436Crossref PubMed Scopus (29) Google Scholar). Therefore, the principles of neuron-immune signaling may have conserved elements across evolution, and investigation of the parallels between organisms could lead to new insights into crosstalk between these two ancient systems. The evidence for communication between the nervous and immune systems extends to non-mammalian organisms, including the roundworm, C. elegans. As they feed on bacteria, C. elegans must quickly distinguish between pathogenic and beneficial microbes. In these worms, the sensory nervous system plays a key role in directly detecting bacterial pathogens and mediating avoidance behavior (Meisel et al., 2014Meisel J.D. Panda O. Mahanti P. Schroeder F.C. Kim D.H. Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans.Cell. 2014; 159: 267-280Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Zhang et al., 2005Zhang Y. Lu H. Bargmann C.I. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans.Nature. 2005; 438: 179-184Crossref PubMed Scopus (473) Google Scholar). Neurons also regulate immune responses at the cellular and molecular level in C. elegans. Specific sensory neuron subtypes expressing the GPCRs octopamine receptor-1 (OCTR-1) or neuropeptide receptor resemblance-1 (NPR-1) regulate immune defenses in C. elegans through modulation of innate immune signaling, microbial killing pathways, and the unfolded protein response (Styer et al., 2008Styer K.L. Singh V. Macosko E. Steele S.E. Bargmann C.I. Aballay A. Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR.Science. 2008; 322: 460-464Crossref PubMed Scopus (155) Google Scholar, Sun et al., 2011Sun J. Singh V. Kajino-Sakamoto R. Aballay A. Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes.Science. 2011; 332: 729-732Crossref PubMed Scopus (153) Google Scholar). Neuro-endocrine signaling through an insulin-like neuropeptide INS7 also regulates clearance of bacterial infection (Kawli and Tan, 2008Kawli T. Tan M.W. Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling.Nat. Immunol. 2008; 9: 1415-1424Crossref PubMed Scopus (80) Google Scholar). In the skin, neuronal expression of a TGFβ homolog in C. elegans promotes antimicrobial peptide expression during fungal pathogen exposure (Zugasti and Ewbank, 2009Zugasti O. Ewbank J.J. Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-beta signaling pathway in Caenorhabditis elegans epidermis.Nat. Immunol. 2009; 10: 249-256Crossref PubMed Scopus (122) Google Scholar). In the intestine of C. elegans, neural signaling through acetylcholine induces Wnt pathway genes that upregulate antimicrobial C-type lectins and lysozymes during bacterial infection (Labed et al., 2018Labed S.A. Wani K.A. Jagadeesan S. Hakkim A. Najibi M. Irazoqui J.E. ). Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection.Immunity. 2018; 48: 963-978.e963Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). In Drosophila, sensory neuron signaling through Activin-β (a TGF-β family ligand) regulates proliferation and adhesion of hemocytes (Makhijani et al., 2017Makhijani K. Alexander B. Rao D. Petraki S. Herboso L. Kukar K. Batool I. Wachner S. Gold K.S. Wong C. et al.Regulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons.Nat. Commun. 2017; 8: 15990Crossref PubMed Scopus (27) Google Scholar). In zebrafish, olfactory sensory neurons rapidly regulate CD8+ T cell responses during rhabdovirus infections in a tropomyosin receptor kinase A (TrkA)-dependent manner (Sepahi et al., 2019Sepahi A. Kraus A. Casadei E. Johnston C.A. Galindo-Villegas J. Kelly C. García-Moreno D. Muñoz P. Mulero V. Huertas M. Salinas I. Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner.Proc. Natl. Acad. Sci. USA. 2019; 116: 12428-12436Crossref PubMed Scopus (29) Google Scholar). Therefore, the principles of neuron-immune signaling may have conserved elements across evolution, and investigation of the parallels between organisms could lead to new insights into crosstalk between these two ancient systems. The nervous system is poised to detect and respond to external threats, including invasion by bacterial, fungal, viral, and parasitic pathogens. Neurons can directly sense pathogenic ligands and rapidly communicate with macrophages, neutrophils, dendritic cells (DCs), and innate lymphoid cells (ILCs) to modulate antimicrobial responses (Figure 1). Neuro-immune interactions orchestrate the response to bacterial infections within several major barrier tissues, including the skin, the lung, and the intestinal tract. In the skin, cutaneous nerves play an integral role in modulating bacterial host defenses. During Staphylococcus aureus skin infections, Nav1.8+ and TRPV1+ nociceptor neurons directly sense bacteria through detection of N-formylated peptides and the pore-forming toxin α-hemolysin (Chiu et al., 2013Chiu I.M. Heesters B.A. Ghasemlou N. Von Hehn C.A. Zhao F. Tran J. Wainger B. Strominger A. Muralidharan S. Horswill A.R. et al.Bacteria activate sensory neurons that modulate pain and inflammation.Nature. 2013; 501: 52-57Crossref PubMed Scopus (426) Google Scholar). On the one hand, these nociceptors signal to the CNS to produce the unpleasant sensation of pain (Blake et al., 2018Blake K.J. Baral P. Voisin T. Lubkin A. Pinho-Ribeiro F.A. Adams K.L. Roberson D.P. Ma Y.C. Otto M. Woolf C.J. et al.Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314.Nat. Commun. 2018; 9: 37Crossref PubMed Scopus (46) Google Scholar). Concurrently, nociceptors secrete neuropeptides from their peripheral nerve terminals that regulates immunity. In S. aureus infection, nociceptors release the neuropeptide CGRP in the skin, which inhibits macrophage production of tumor necrosis factor (TNF)-α, reduces monocyte influx, and suppresses draining lymph node hypertrophy (Chiu et al., 2013Chiu I.M. Heesters B.A. Ghasemlou N. Von Hehn C.A. Zhao F. Tran J. Wainger B. Strominger A. Muralidharan S. Horswill A.R. et al.Bacteria activate sensory neurons that modulate pain and inflammation.Nature. 2013; 501: 52-57Crossref PubMed Scopus (426) Google Scholar). Streptococcus pyogenes is another major cause of skin and soft tissue infections, including necrotizing fasciitis (flesh-eating disease), characterized by “pain out of proportion” with other manifestations. In a mouse model of necrotizing fasciitis, S. pyogenes exploits a pain-driven neuro-immune circuit to facilitate its survival (Pinho-Ribeiro et al., 2018Pinho-Ribeiro F.A. Baddal B. Haarsma R. O’Seaghdha M. Yang N.J. Blake K.J. Portley M. Verri W.A. Dale J.B. Wessels M.R. et al.Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection.Cell. 2018; 173: 1083-1097.e1022Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). S. pyogenes secretes streptolysin S, a pore-forming toxin that activates TRPV1+ neurons to produce pain. These neurons in turn release CGRP, which suppresses neutrophil recruitment and inhibits both human and mouse neutrophil killing of S. pyogenes. In S. pyogenes soft tissue infections, Botulinum neurotoxin A (BoNT/A) injections to block neuro-immune communication or administration of a CGRP receptor antagonist significantly improved the outcome of infection (Pinho-Ribeiro et al., 2018Pinho-Ribeiro F.A. Baddal B. Haarsma R. O’Seaghdha M. Yang N.J. Blake K.J. Portley M. Verri W.A. Dale J.B. Wessels M.R. et al.Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection.Cell. 2018; 173: 1083-1097.e1022Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). The lungs and respiratory tract are densely innervated by sensory and autonomic neurons that mediate cough and bronchoconstriction. Neuro-immune crosstalk also regulates pulmonary bacterial host defenses. Vagal nociceptor neurons suppress γδ T cell and neutrophil responses during lethal bacterial lung infections (Baral et al., 2018Baral P. Umans B.D. Li L. Wallrapp A. Bist M. Kirschbaum T. Wei Y. Zhou Y. Kuchroo V.K. Burkett P.R. et al.Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia.Nat. Med. 2018; 24: 417-426Crossref PubMed Scopus (106) Google Scholar). In methicillin-resistant S. aureus (MRSA) pneumonia, ablation of TRPV1+ vagal sensory neurons leads to improved survival, core body temperature maintenance, and bacterial clearance. TRPV1+ neurons block the ability of neutrophils to infiltrate the lungs and survey the parenchyma for pathogens. TRPV1+ neurons also regulate lung homeostatic levels of γδ T cells, an important source of interleukin (IL)-17, to protect against MRSA infection. Treatment of mice with resiniferatoxin (RTX), a chemical that ablates TRPV1+ neurons, or blockade of CGRP signaling with a peptide antagonist significantly enhances survival and bacterial clearance. Therefore, nociceptor neurons suppress local immunity in respiratory tract infections, and targeting this signaling could lead to novel treatments for bacterial pneumonia. The intestine is densely innervated and constantly exposed to microbial stimuli. Gut-innervating neurons and gut-resident enteric neurons also actively participate in host defense. Recent work has found that enteric neurons in the myenteric plexus are a major source of IL-18, which drives host protection against the enteric pathogen Salmonella enterica serovar Typhimurium (Jarret et al., 2020Jarret A. Jackson R. Duizer C. Healy M.E. Zhao J. Rone J.M. Bielecki P. Sefik E. Roulis M. Rice T. et al.Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity.Cell. 2020; 180: 50-63.e12Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Enteric neuron-derived IL-18 acts on intestinal goblet cells to induce the expression of antimicrobial peptides (AMPs) in the colon to protect against Salmonella infection. Gut-innervating nociceptor neurons (TRPV1+ Nav1.8+) also defend against Salmonella infection by crosstalk with epithelial cells and the intestinal microbiota (Lai et al., 2020Lai N.Y. Musser M.A. Pinho-Ribeiro F.A. Baral P. Jacobson A. Ma P. Potts D.E. Chen Z. Paik D. Soualhi S. et al.Gut-Innervating Nociceptor Neurons Regulate Peyer’s Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense.Cell. 2020; 180 (Published online December 5, 2019): 33-49.e22https://doi.org/10.1016/j.cell.2019.11.014Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Salmonella invade the small intestine through intestinal microfold (M) cells, which are specialized epithelial cells within Peyer’s patch (PP) follicle-associated epithelium (FAE). Nociceptor neurons signal via CGRP to reduce the numbers of M cells, thus removing the gates of entry for these pathogens. Nociceptor signaling also maintains levels of segmented filamentous bacteria (SFB) in the small intestine—an intestine-resident microbe that provides resistance against Salmonella colonization and invasion. Gut-innervating tyrosine hydroxylase-expressing (TH+) sympathetic neurons also play a key role in host defense within the intestine. During homeostasis, TH+ neurons signal to resident muscularis macrophages (MMs) through the beta-2 adrenergic receptor (β2AR) to polarize the MMs toward a tissue-protective M2-like phenotype (Gabanyi et al., 2016Gabanyi I. Muller P.A. Feighery L. Oliveira T.Y. Costa-Pinto F.A. Mucida D. Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages.Cell. 2016; 164: 378-391Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). During gastrointestinal infection caused by Salmonella and other enteric pathogens, these macrophages protect enteric neurons from caspase-11-dependent death through their expression of arginase and protective polyamines (Matheis et al., 2020Matheis F. Muller P.A. Graves C.L. Gabanyi I. Kerner Z.J. Costa-Borges D. Ahrends T. Rosenstiel P. Mucida D. Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss.Cell. 2020; 180: 64-78.e16Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Therefore, neuro-immune crosstalk is a major component of host immunity and protection against enteric pathogen invasion. Nociceptor neurons drive protective skin immunity against fungal pathogens. In Candida albicans skin infections, TRPV1+ nociceptors drive IL-23 production by CD301b+ dermal dendritic cells, which induces γδ T cell production of IL-17 and protective immunity against C. albicans (Kashem et al., 2015Kashem S.W. Riedl M.S. Yao C. Honda C.N. Vulchanova L. Kaplan D.H. Nociceptive Sensory Fibers Drive Interleukin-23 Production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity.Immunity. 2015; 43: 515-526Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). This protective response is mediated by CGRP, as its injection was sufficient to restore IL-23 and IL-17 responses in nociceptor ablated mice (Figure 2). Nociceptor neurons respond to fungi by detection of C. albicans-derived β-glucan through Dectin-1 (Maruyama et al., 2018Maruyama K. Takayama Y. Sugisawa E. Yamanoi Y. Yokawa T. Kondo T. Ishibashi K.I. Sahoo B.R. Takemura N. Mori Y. et al.The ATP Transporter VNUT Mediates Induction of Dectin-1-Triggered Candida Nociception.iScie