Introduction

Breathing is an autonomic process that involves the exchange of gases with the external environment through the respiratory tract, regulated by the nervous system [1, 2]. Simultaneously, various pathogens, pollutants and other potential hazards are present in the air, continuously entering the respiratory tract with each breath [3]. The ability to monitor and respond in a timely manner to potential hazards within the respiratory tract is critical to the survival of this species.

Neuroimmune interactions enable rapid sensing and response to pathogens. Various types of neurons project into the respiratory tract and form synapses in different respiratory areas [4], including the trigeminal, olfactory, glossopharyngeal, vagus, dorsal root nerves of the spinal cord, and sympathetic chains. A large number of immune cells are also resident in the respiratory tract, such as mast cells [5, 6], dendritic cells [7], group 2 innate lymphoid cells (ILC2s) [8] and interstitial macrophages [9, 10], and they are located in close proximity to nerve fibres. After sensing pathogens, these immune cells can rapidly transmit immune signals to neurons [11, 12]. The nervous and immune systems share pattern recognition receptors (PRRs) [13], with neurons expressing receptors for pathogens and immune factors, such as TLR4, TLR5, NOD3, NLRX1, DHX58, LRRFIP1, etc. Thus, sensory neurons can directly sense pathogen-associated molecular patterns (PAMPs) through transient receptor potential (TRP) ion channels and the expression of PRRs. For example, TRPA1 and TRPV1 can directly detect lipopolysaccharide (LPS) from Gram-negative bacteria [14]. Furthermore, neurons could also function as second-order neurons, indirectly sensing pathogens by forming recognition units in collaboration with respiratory epithelial cells, such as pulmonary neuroendocrine cells (PNECs), brush cells, solitary chemosensory cells (SCCs) and tastebud cells. These cells express specific receptors that enhance the ability to sense pathogens compared to free nerve endings. These neuroepithelial–immune interactions enhance the ability of nerves to detect various types and quantities of pathogens in the respiratory system. Neuroimmune interactions in the respiratory tract have been implicated in various disease conditions, including viral infections [15, 16], bacterial infections [17], acute lung injury [18], allergic airway inflammation [19], lung fibrosis [20] and more [21]. These neurons relay signals to different areas of signal processing and integration within the central nervous system (CNS) [22], where signals from different neurons are harmoniously coordinated, and efferent neurons are subsequently activated to perform a precise immune response.

Here, we summarise the latest findings on neuroimmune interactions within the respiratory system. In addition, we discuss strategies to translate these interactions into therapeutic strategies for respiratory diseases, particularly in the field of bioelectronic medicine.

Neuroanatomy of the respiratory tract

Neurons projected to the respiratory tract are mainly from the olfactory nerve (I), trigeminal nerve (V), glossopharyngeal nerve (IX), vagus nerve (X), dorsal root ganglia (DRG), sympathetic ganglia and intrinsic neurons from peripheral organs such as the oesophagus and lungs (figure 1a). The synaptic terminals of these neurons exhibit a hotspot distribution in the respiratory tract, preferentially located in locations conducive to monitoring respiratory status, such as the nasal epithelium, nasal roof, posterior nasopharyngeal region, larynx, tracheochondral space and airway branches.

FIGURE 1

Innervation of the respiratory tract. Neurons projected to the respiratory tract are mainly from the olfactory nerve (cranial nerve I), trigeminal nerve (cranial nerve V), glossopharyngeal nerve (cranial nerve IX), vagus nerve (cranial nerve X), dorsal root ganglia (DRG), sympathetic ganglia and intrinsic neurons from peripheral organs such as the oesophagus and lungs. The sympathetic ganglia can be further divided into the superior cervical ganglion (SCG), the stellate ganglia (SG) and the thoracic sympathetic chain ganglion (TSG), each of which projects differently to the respiratory tract. The synaptic terminals of sensory neurons are hotspots distributed in the respiratory tract, including from pulmonary neuroendocrine cells, brush cells, solitary chemosensory cells and tastebuds. Neural recognition of pathogens is expanded through the expression of recognition receptors on these cells. TG: trigeminal ganglion; Pa5: paratrigeminal nucleus; PG: petrosal ganglion; JG: jugular ganglion; NG: nodose ganglion; NTS: solitary tractus nucleus; DMV: dorsal motor nucleus of the vagus nerve; Amb: nucleus ambiguus; IS: inferior salivatory nucleus.

Trigeminal nerve

The ophthalmic and maxillary nerves of the trigeminal nerve project into the nasal epithelium in the nasal cavity. The trigeminal nerve is a heterogeneous nerve. Its sensory neurons are unique, with most of the cell bodies located in the trigeminal ganglia and the rest in the midbrain trigeminal nucleus of the brain [23]. Stimuli are detected by free nerve endings in the nasal epithelium [24]. In the nasal epithelium, while certain lipophilic stimuli (e.g. peppermint, ammonia) can be detected by the free intraepithelial nerve endings of the trigeminal nerve through intrinsic TRP channels, including TRPV1 (capsaicin), TRPA1 (mustard oil, etc.) and TRPM8 (peppermint), the ability of free nerve endings to penetrate the barrier and contact stimuli is limited. Thus, the trigeminal nerve enhances its ability to detect stimuli by projecting onto specialised SCCs [25, 26]. This enhances the ability of the trigeminal nerve to detect various types and quantities of pathogens [27].

Olfactory nerve

The olfactory nerve is located mainly at the top of the nasal cavity. It is made up of pure sensory neurons and are bipolar neurons that express two olfactory receptors: odour receptors and trace amine-associated receptors [28]. These receptors closely integrate signals to sense >1 trillion molecular stimuli in the air [29], transmitting the signals through the olfactory bulb to the olfactory cortex. When a harmful or toxic gas is detected, this triggers an aversive emotional response that mediates avoidance and defensive behaviour. Multiple respiratory pathogens target olfactory neurons, so loss of smell has been observed in various respiratory diseases [30].

Glossopharyngeal nerve

The glossopharyngeal nerve primarily innervates the pharynx in the respiratory tract. It is also a heterogeneous nerve, with its sensory neurons being pseudounipolar neurons. The cell bodies of the sensory neurons are located in the petrosal ganglion, with one end of the neuron extending to the pharynx, transmitting recognition information to the paratrigeminal nucleus (Pa5) and the nucleus of the solitary tract (NTS) [31, 32]. The glossopharyngeal nerve is primarily composed of sensory neurons, capable of detecting the mucosa of the throat, blood pressure, eardrum and tonsils. It is considered to be an important component of neuroimmune surveillance of the oral cavity [33]. Recent studies have found that γ-aminobutyric acid receptor subunit α1 (GABRA1+) petrosal neurons located in the posterior region of the nasopharynx sense influenza virus infection, inducing sickness behaviour [15]. Additionally, the motor neurons of the glossopharyngeal nerve, with cell bodies located in the dorsal motor nucleus of the vagus, nucleus ambiguus and inferior salivatory nucleus [34] extend synapses to the periphery, regulating swallowing, saliva release and exerting parasympathetic functions [35]. However, it remains unclear how motor neurons of the glossopharyngeal nerve directly regulate peripheral immune responses. Nevertheless, they can influence the drainage and cleansing of the pharyngeal mucosa through the movement of pharyngeal muscles and secretion of salivary glands, thereby impacting mucosal immune responses. Additionally, the glossopharyngeal and vagus nerves are intimately related, thus it has the potential to regulate immune responses by affecting the vagus nerve.

Vagus nerve

The vagus nerve connects visceral tissues with the CNS, mediates internal sensory and physiological regulation in the body and responds to external stimuli [36]. The vagus nerve is the most extensive nerve that projects into the respiratory tract, from the pharynx to the alveoli. The vagus nerve is made up of sensory neurons and motor neurons that move together in the same bundle, with sensory neurons making up ∼80% of the total number of neurons. The cell bodies of sensory neurons are located in the nodose and jugular ganglia [37]. Ganglia contain not only neurons, but also glial cells, Schwann cells, endothelial cells and immune cells, which are collectively involved in signal recognition, axon regeneration and transmission [38, 39].

Vagal sensory neurons project into the respiratory tract and are primarily located in the right vagus nerve [40]. Vagal sensory neurons have a pseudounipolar structure. One end extends to the NTS or Pa5, while the other end extends to peripheral organs. Neurons projecting to the NTS are predominantly located in the nodose ganglia, and their axons are predominantly projected to the trachea, across the entire lung and onto the bronchial/bronchioles, vasculature/lymphatic, alveoli and PNECs [41, 42]. Sensory neurons projected to Pa5 originate from neurons located in the jugular ganglia, and their axons project mainly to the pharynx and trachea, and to a small extent to the bronchi and alveoli and vessels of various sizes [43]. Vagal sensory neurons projected to the trachea and lungs originate mainly from the nodose ganglia, and ∼65% of tracheal sensory neurons originate from the nodose ganglia, with a few from the jugular ganglia. Similarly, sensory neurons that project to the lungs also have their central projections in the NTS [22, 40, 42]. Most vagal sensory neurons are unmyelinated, slow-conduction C-fibres that can be activated by a variety of mechanical and chemical stimuli to enable the transmission of peripheral immune messages to the brain. Although vagus neurons make up only a small portion of the nervous system, vagus neurons exhibit a high degree of heterogeneity, with different subpopulations of neurons having different important functions and can be divided into ≥37 clusters [44]. Vagal neurons that control different tissues exhibit different transcriptome patterns, especially in neurons that control the lungs and oesophagus, where they show a distinct subset distribution [22], indicating their functional independence [45]. The cell bodies of vagus motor neurons are located in the dorsal motor nucleus of the vagus and nucleus ambiguus. Their axons project into the respiratory tract, and their nerve endings release acetylcholine (ACh) directly onto target cells or act on intrinsic neurons within the respiratory tract [46].

Dorsal root ganglia

Sensory neurons in DRGs are classified as pseudounipolar neurons. Neurons that project to the lungs are predominantly located in the DRG segment T1–T3, project to bronchial tubes and blood vessels >376 mm in diameter, and project to neuroepithelial bodies. The secretion of CCL2 by vascular endothelial cells is crucial for early neural recognition [47]. However, projections to alveoli and small blood vessels were not observed [43]. Further confirmation is required to determine if the DRG can be projected onto the trachea.

Sympathetic neurons

The sympathetic neurons projected to the respiratory tract mainly originate from the superior cervical ganglia, stellate ganglia and thoracic sympathetic chain ganglia in the T2–T4 segments [40]. These neurons exhibit different projection sites along the respiratory tract. Specifically, the superior cervical ganglion protrudes into the upper or middle part of the cervical trachea, and the stellate ganglion protrudes primarily into the inferior trachea, but also to the lungs. The thoracic sympathetic links of the T2–T4 segments extend into the lungs [40]. Similar to the fact that vagus nerve sensory neurons originate mainly on the right side, sympathetic neurons projected into the respiratory tract are also mainly distributed on the right side, accounting for ∼70% of the distribution [41].

Intrinsic neuronsPulmonary intrinsic neurons

The intrinsic ganglion cells in the lungs originate in the area of the hindbrain (vagal) of the neural crest [48]. Cholinergic clusters are distributed around the proximal airways within the lung, with 75% of these neurons receiving projections from calbindin+ fibres originating in the nucleus ambiguus [46], mediating functions such as bronchoconstriction.

Oesophageal myenteric neurons

Intrinsic neurons are present in the oesophageal intestinal plexus. These neurons within the oesophagus can receive projections from the vagus nerve. They project to the smooth muscle cells of the trachea and account for 6% of the total nerves projected to the central airway smooth muscle cells [49]. These neurons belong to nonadrenergic noncholinergic parasympathetic neurons, most of which release vasoactive intestinal peptide (VIP) and nitric oxide (NO), which mediate the relaxation of airway smooth muscle cells.

Neuroimmune recognition of sensory neurons in the respiratory system

Sensory neurons have the ability to detect pathogens and immune mediators through free nerve endings (figure 2). They can also act as second-order neurons to indirectly recognise pathogens by cooperating with respiratory epithelial cells such as PNECs, brush cells, SCCs and tastebuds to form recognition units. Neuroimmune–epithelial interactions contribute to pathogen recognition and immunomodulation. Ongoing studies have identified various key detection sites within the respiratory tract and revealed different compositional patterns of these neuroepithelial recognition units (figure 3).

FIGURE 2

Sensory neurons directly or indirectly perceive danger signals, with the vagus nerve as the example. Sensory neurons directly sense pathogens in a variety of ways. a) First, sensory neurons directly perceive pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) through the expression of pattern recognition receptors (PRRs). Sensory neurons utilise the expression of classical PRRs, such as toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), nucleotide-binding and oligomerisation domain (NOD)-like receptors (NLRs), prostaglandin E receptor (EP)3 and FcεR1α to directly sense pathogens and immune mediators. As these receptors are activated, intracellular NF-κB and mitogen-activated protein kinase (MAPK) signalling pathways are initiated, leading to an increase in intracellular calcium (Ca2+) and sodium (Na+) flux, thereby activating neuronal signal transduction. These ion fluxes also activate ion channels within neurons, propelling neurons to further activation and enhancing sensitisation. b) Second, sensory neurons express a variety of ion channel receptors on their surface, including transient receptor potential (TRP) channels, purinergic P2X channels, and mechanosensitive ion channels. For example, transient receptor potential cation channel subfamily A member 1 (TRPA1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) can directly detect lipopolysaccharide (LPS) in Gram-negative bacteria and respond to thermal stimuli. Recognition of these stimuli induces channel opening, influx of Ca2+ and Na+, and rapid changes in neuronal membrane potential, resulting in rapid activation of neurons. c) Third, sensory neurons can couple PRRs to ion channels to comediate recognition responses to pathogenic substances. Examples include the conjugation of TLR4 to TRPV1, TLR7 to TRPA1 and TLR3 to TRPV1. By coupling PRRs expressed on neurons with ion channels, the immune signals transmitted by immune-related receptors are rapidly converted into neuroelectrical signals, overcoming the slow transmission of immune signals. ss: single strand; ds: double strand; MDP: muramyl dipeptide.

FIGURE 3

Neuroepithelial interactions contribute to the recognition and regulation of pathogens. CGRP: calcitonin gene-related peptide; ACh: acetylcholine; NE: norepinephrine; 5-HT: 5-hydroxytryptamine; P2RY1: P2Y purinoceptor 1; SP: substance P; PNECs: pulmonary neuroendocrine cells; Pvalb: parvalbumin; Na: sodium; K: potassium; TRP: transient receptor potential; DRG: dorsal root ganglion; ATIII: alveolar type III cells; Npy2r: neuropeptide Y receptor type 2.

Sensory neurons detect pathogens or immune mediators in the periphery, and recognition signals are transmitted in an anterograde manner to the CNS. At the same time, the action potential can also be retrograde back to the peripheral end of the branch point, resulting in the release of neuropeptides (calcitonin gene-related peptides, substance P) by axon reflex to induce neurogenic inflammation [50]. Recognition of immune mediators also leads to sensitisation of fibres. Sensitisation means that normally harmless mechanical and thermal stimuli can now activate nociceptive neurons, further amplifying the inflammatory response [51].

Sensory neurons can act as first-order sensory neurons to directly recognise internal changes and external stimuli within the respiratory tract. Sensory neurons express various types of receptors that can detect pathogens and inflammatory mediators released by immune cells or other cells. Sensory neurons directly sense pathogens in different ways. Firstly, sensory neurons directly sense PAMPs or damage-associated molecular patterns [52] (figure 2a). For instance, GABRA1+ petrosal neurons directly detect the induction of prostaglandin (PG)E2 due to influenza virus through the expression of PGE2 receptor 3 (EP3) [15]. TRPV1+ vagal neurons directly sense IgE produced from allergic airway inflammation by expressing FcεR1α [53]. Simultaneously, sensory neurons utilise the expression of classical PRRs, such as toll-like receptors (TLRs), C-type lectin receptors, RIG-I-like receptors and nucleotide-binding and oligomerisation domain-like receptors, to directly sense pathogens and immune mediators. As these receptors are activated, intracellular NF-κB and mitogen-activated protein kinase signalling pathways are initiated, leading to an increase in intracellular calcium (Ca2+) and sodium ion flux, thereby activating neuronal signal transduction. These ion fluxes also activate ion channels within neurons, propelling neurons to further activation and enhancing sensitisation. Secondly, sensory neurons can also directly identify pathogen-related substances using TRPs (figure 2b). For example, TRPA1 and TRPV1 can directly detect LPS [14]. Thirdly, sensory neurons can couple PRRs with TRP channels to jointly mediate pathogen recognition responses, rapidly convert immune signals into neural excitation and induce rapid neuronal activation (figure 2c). TLR4 enhances the activation of TRPV1 in sensory neurons and inhibits activation-induced internalisation of TRPV1 and subsequent lysosomal degradation, thereby preventing TRPV1 desensitisation [54]. The interaction between PRR and TRP has also been observed in other neuronal recognition processes. Sensory neurons sense exogenous miRNAs through TLR7 and its coupling to TRPA1, inducing rapid inward currents and action potentials, resulting in rapid neuronal excitation [55]. In addition, the interaction between PRR and TRP has been found to be a broad mechanism of rapid cellular activation, not limited to neurons. For example, in endothelial cells, TLR4 induces TRPC6-dependent Ca2+ signalling, leading to rapid activation of endothelial cells [56]. There are other ion channels such as TLR2–TRPA1 in smooth muscle cells, TLR2/4–TRPM8 in neuroblastoma, TLR2/4–TRPV1 in monocytes and macrophages [57]. This overcomes the slow transmission of immune signalling. Crucially, sensory neurons sense pathogens or inflammatory mediators, leading to neuronal sensitisation and lowering the activation threshold, making them more susceptible to activation. This enhances the input strength of sensory neuronal signals, making neurons more sensitive. These activated neurons further promote the CNS response to stimuli, leading to a range of physiological responses such as pain, fever and inflammation [58].

Furthermore, neurons can also act as secondary neurons to indirectly recognise pathogens by cooperating with respiratory epithelial cells (e.g. PNECs, brush cells, SCCs and tastebuds) to form recognition units. These cells act as first-order sensory cells that provide signals to sensory neurons. These epithelial cells are responsible for detecting pathogens or pathogen-induced molecules, with the subsequent release of neurotransmitters to activate projected sensory neurons. For example, tracheal brush cells expressing bitter taste receptors can sense P. aeruginosa, resulting in the release of ACh, which activates adjacent sensory nerve endings to release calcitonin gene-related peptide (CGRP) and substance P, mediating plasma extravasation and neutrophil recruitment [59]. PNECs are the key recognising cells, albeit in a small fraction, accounting for <1% of total epithelial cells. They play a pivotal role in both physiological and pathological conditions. Once a lack of oxygen is felt, they can release CGRP to alleviate lung damage [60]. In addition, PNECs induce the recruitment of macrophages by releasing CGRP, thereby regulating the immune environment of the lungs. When PNECs are dysregulated and release excess CGRP, it leads to an increase in lung macrophages and subsequent lung damage [61]. However, it is unclear how PNECs transmit signals to sensory neurons and how neurons regulate PNECs.

The human respiratory tract extends from the nostrils to the alveoli of the lungs, with specific bacterial communities inhabiting different locations [3], monitored by neurons projected to the respiratory tract. The specificity of the neuroimmune response, whether it is limited to pathogens or extends to commensal micro-organisms as well, is unclear. We believe that sensory neurons can distinguish between pathogens and commensals. There are two ways in which the nervous system triggers an immune response: direct neural recognition, and recognition of pathogens by epithelial cells or immune cells followed by activation of neurons [4, 27, 59, 62]. In the first mechanism, direct neural recognition, diverse pathogen receptors expressed by neurons can directly recognise pathogens, leading to the initiation of neuroimmune responses. For commensals present in the lungs, they have already established a steady interaction with the nervous system, resulting in the nervous system possessing corresponding activation thresholds. The desensitisation mechanism of neurons is mediated by TRP and G protein-coupled receptors (GPCRs) [63, 64]. Specifically, GPCRs undergo desensitisation through phosphorylation by G protein-coupled receptor kinases, after which the phosphorylated receptors are bound by arrestin proteins, blocking further stimulation of G proteins and downstream signalling pathways [63]. Dynamin-2 also plays a significant role in the internalisation and desensitisation of GPCRs [65]. A few members of the PRR family belong to the GPCR family, such as formyl peptide receptors and protease-activated receptor 1, which respectively recognise formyl peptides and protease V8 released by Staphylococcus aureus [66, 67]. The influx of Ca2+ through TRPV1 channels leads to two desensitisation phenomena: “acute” desensitisation, which weakens the response during continuous application, and “tachyphylaxis”, which reduces the response to repeated exposure [64]. Additionally, neurotransmitter receptors can undergo desensitisation, inhibiting direct signal transmission between neurons. For example, under sustained receptor activation, nicotinic ACh receptors (nAChRs) can undergo reversible desensitisation [68]. These may lead to neuronal tolerance to commensals. However, there are also some commensals with potential pathogenicity. When respiratory homeostasis is disrupted, these commensal organisms proliferate extensively, disrupting the stability of the neuroimmune system. If the activation thresholds are surpassed, the neuroimmune response will also target commensals. The second mechanism involves neural activation after recognition by epithelial cells and immune cells. This recognition of pathogens depends on epithelial cells and immune cells, both of which have mechanisms to distinguish between pathogens and commensals [69, 70].

Neuroimmune regulation in the respiratory systemPulmonary parasympathetic inflammation reflex

Both sensory neurons and motor neurons contribute to immune regulation, which helps modulate the local inflammatory microenvironment during infection, promoting pathogen clearance. In particular, sensory neurons can transmit signals to the central nervous system, activate specific brain regions and trigger specific efferent nerve excitations. Currently, the theory of immune regulation of respiratory efferent nerves is the “pulmonary parasympathetic inflammatory reflex” [71]. The parasympathetic nervous system promotes physiological and pathological processes in the lungs by releasing active substances such as ACh, VIP, neuromedin U (NMU), etc. These neuropeptides and neurotransmitters act on a variety of cells, including macrophages, T-cells, T follicular helper cells, B-cells, red blood cells, type II alveolar epithelial cells and airway epithelial cells. ACh, in particular, can interact with nAChRs and muscarinic acetylcholine receptors (mAChRs) expressed on these cells. In addition, ACh in the lungs comes not only from the vagus nerve, but also from airway epithelial cells, and immune cells such as B-cells and T-cells can also produce ACh [11, 72, 73]. Neuroepithelial–immune interactions work together to promote ACh signalling in physiological and pathological processes in the lungs. Traditionally, activation of nAChR in the airways has been associated with inducing anti-inflammatory effects, while activation of mAChR has been thought to cause pro-inflammatory effects [74]. Regarding the role of α7nAChR, the common concept is that it is an important component of the cholinergic anti-inflammatory pathway. Activation of α7nAChR is thought to downregulate the production of pro-inflammatory factors such as tumour necrosis factor (TNF)-α. However, it was found that the effects of α7nAChR activation depended on the cell type and disease model [18–20, 75–82]. Activation of α7nAChR can lead to different regulatory roles in various cellular and disease models (table 1). For example, activation of α7nAChR upregulates the inflammatory response of megakaryocytes. Lung megakaryocytes produce ∼50% of platelets in the body and exhibit significant differences in gene expression compared to bone marrow megakaryocyte cells [83]. Lung megakaryocytes express fewer mature megakaryocyte markers, and their gene expression pattern resembles that of antigen-presenting cells. Lung megakaryocytes can induce the activation of CD4+ T-cells both in vitro and in vivo in a major histocompatibility complex II-dependent manner. Additionally, the immune phenotype can be altered based on the tissue environment, such as pathogen challenge and interleukin IL-33 [84]. This means that lung megakaryocytes act as early responders regulated by vagal-α7nAChR signalling (our unpublished data). In addition, α7nAChR is expressed in lung fibroblasts. Activation of α7nAChR in human fibroblasts enhances fibrosis genes (Acta2, Colla1) and promotes pulmonary fibrosis [20]. Vagus-α7nAChR signalling in different cells ensures the ability to respond to different stages of infection caused by various pathogens, coordinating the balance between pathogen recognition, clearance and tissue repair.

TABLE 1

Vagus-α7 nicotinic acetylcholine receptors (α7nAChR) signalling plays different roles in response to different pathogens and stimuli

Neuroimmune interaction in respiratory disease

The nervous system employs various types of neurons that project to different locations within the respiratory tract, interacting with local respiratory epithelial cells and immune cells, continually monitoring and regulating the respiratory homoeostasis. However, this homoeostasis can also be disrupted by a range of factors, including bacteria, viruses, other pathogens and allergens present in the air, leading to respiratory infections, inflammation and tissue damage. Neurons project to different locations in the respiratory tract, targeting various pathogens, allergens and environmental exposures. These neurons can function independently or cooperatively to maintain the health of both the respiratory tract and the nervous system.

Bacterial infection

Currently, the process of neural recognition and its mediation of neuroimmune responses to various bacteria has been discovered. Here, we primarily discuss S. aureus, P. aeruginosa, Bacillus anthracis and M. tuberculosis. In the nasal epithelium (figure 4a), irritants can be detected at the free intraepithelial nerve endings of the trigeminal nerve. At the same time, the trigeminal nerve enhances its ability to detect irritants by projecting to specialised SCCs [27]. SCCs express multiple types of receptors, including the bitter taste receptor T2R, which can identify acyl-homoserine lactones produced by Gram-negative bacteria. SCCs also express choline O-acetyltransferase (CHAT) [85, 86], which enables signal transmission through acetylcholine (ACh), activating the trigeminal nerve. This activation leads to the release of CGRP and substance P through axon reflex, triggering neurogenic inflammation, which affects vascular endothelial cells and results in increased blood flow, vascular leakage and oedema. This process facilitates the recruitment of inflammatory leukocytes [58]. The arrival of leukocytes aids in clearing bacteria, thereby combating bacterial invasion.

FIGURE 4

Examples of neuroimmune interactions in the respiratory tract. a) Bacterial infection: sensory neurons act as second-order neurons that receive input from respiratory epithelial cells, such as solitary chemosensory cells (SCCs). SCCs sense acyl-homoserine lactones (AHLs) [27, 87] produced by Gram-negative bacteria through bitter taste receptors (T2R). The release of acetylcholine (ACh) from SCCs activates trigeminal sensory neurons, triggering axonal reflexes, leading to the release of calcitonin gene-related peptide (CGRP) and substance P (SP) from peripheral nerve endings and neurogenic inflammation. Nerves can sense bacterial infections in a variety of ways. One way to do this is to identify pathogens directly through neurons. For example, transient receptor potential (TRP)V1+ vagus sensory neurons directly recognise Staphylococcus aureus, resulting in the release of CGRP from neurons, which acts on locally infected neutrophils and γδT-cells, inhibiting their inflammatory response. In addition, sensory neurons act as second-order neurons that receive input from respiratory epithelial cells, such as brush cells. Brush cells sense bitter-tasting quorum-sensing molecules (QSM) produced by Pseudomonas aeruginosa through TAS2R taste receptors. Similar to SCCs, the release of ACh from brush cells activates sensory neurons, triggering axonal reflexes, leading to the release of CGRP and SP from peripheral nerve endings and neurogenic inflammation. b) Viral infection: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect olfactory sensory neurons, resulting in olfactory epithelial destruction, leading to anosmia. In addition, SARS-CoV-2 can enter the brain through the olfactory nerve, triggering the activation of microglia and recruiting CD8 T-cells. This activation causes microglia and CD8 cells to aggregate, forming nodules that cause damage to brain tissue. In the case of influenza virus infection, γ-aminobutyric acid receptor subunit α1 (GABRA1+) petrosal neurons located in the posterior region of the nasopharynx expressing prostaglandin E2 (PGE2) receptor 3 (EP3) can sense pathogen-induced PGE2, thereby inducing disease behaviour. c) Allergic airway inflammation: multiple types of nerves are involved in regulating allergic airway inflammation. For the vagus nerve, TRPV1+ vagal neurons can sense IgE produced by the body's immune response through FcεR1 receptors. They release SP, promoting the inflammatory response of type 2 helper (Th2) cells and enhancing the secretion of mucus by goblet cells. Simultaneously, Mrgprc11+ jugular neurons of the vagus nerve activate parasympathetic neurons, leading to the release of ACh, which mediates bronchoconstriction, inducing airway hyperreactivity. The parasympathetic ganglia can also release neuromedin U (NMU), which acts on NMUR1 receptors on group 2 innate lymphoid cells (ILC2), activating them and amplifying allergic inflammation. The parasympathetic nervous system can also negatively regulate ILC2 cells by releasing ACh, which acts on α7 nicotinic acetylcholine receptors (a7nAChR) on ILC2 cells, inhibiting their transformation into inflammatory ILC2 cells. ILC2 cells play a crucial role in the neuroimmune interaction of airway allergic inflammation and can be regulated by various neurons. Regarding sensory neurons, they sense allergic inflammation and release vasoactive intestinal peptide (VIP), which acts on VPAC2 receptors on ILC2 cells, promoting the release of interleukin (IL)-5 and enhancing the inflammatory response of eosinophils. Activated eosinophils can increase airway epithelial nerve density, further leading to airway hyperreactivity. The sympathetic nervous system similarly regulates ILC2 cells by releasing dopamine and norepinephrine, which act on t