Like a guard, dendritic cells (DCs) are the first to sound the alarm when allergens invade. Allergen capture by antigen-presenting cells such as DC cells is the beginning of allergic asthma (7, 8). Nervous system regulates DCs by neuropeptides. Calcitonin gene-related peptide (CGRP) is a neuropeptide secreted by pulmonary neuroendocrine cells (PNECs) mainly in lung. It inhibits maturation of DCs by CGRP receptors expressed in DCs themselves, reducing the activation and proliferation of antigen-specific T cells ( Figure 1 ). In mouse model of ovalbumin (OVA) induced asthma, CGRP-pretreated DCs alleviate inflammation of allergic asthma with reduced eosinophil numbers in bronchoalveolar lavage fluid (26). Interestingly, the nerve cells can also be a whistleblower to allergens thus giving instructions to DCs. A study using skin allergen exposure model found that allergens can directly activate transient receptor potential vanilloid 1 positive sensory neurons in skin, causing itch and pain behaviors. Activated neurons release neuropeptides such as substance P, which can induce the migration of CD301b⁺ DCs into the draining lymph nodes, where the differentiation of Th2 cells is initiated (27). Whether the nervous system is also the first responder of allergens during asthma, thereby triggering the accumulation of dendritic cells and subsequent immune responses needs further exploration. If so, inhibition of sensitization by the allergen to sensory nerve fibers could potentially reduce the activation of pulmonary inflammation during asthma. Besides, antigens can also lead to the variation of innervation, regulating inflammatory infiltration in tissues in an age-related manner. In neonatal mice, exposure to antigens could elevate neurotrophin 4 (NT4) levels of ASMs thus increase ASMs innervation through NT4/TrkB signaling. As a result, persistent AHR appears in adulthood (28) ( Figure 1 ). Therefore, in addition to the familiar antigen-presentation process, the interaction between the nervous system and antigens might be more important during the initial phase of inflammation.

In asthma, mast cells accumulate within or close to epithelium and smooth muscle under the stimulation of allergen (29). Mast cells could mediate acute inflammatory response of asthma by secreting a large number of pro-inflammatory and pro-airway constrictor mediators (29–32). Mast cell is now recognized to be involved in nerve regulation during the development of asthma—with muscarinic M3 receptors on its surface (33). Bronchial stimulation test by methacholine provocations is a classic method used for clinical diagnosis of asthma. Mast cells may play the key role in this response. Under the stimulation of methacholine, mast cells release 5-hydroxytryptamine (5-HT), interact with 5-HT2 receptors in parasympathetic nerves, thus release ACh ( Figure 1 ). ACh, an endogenous neurotransmitter, enhances bronchoconstriction and AHR in house dust mite induced experimental asthma (33). Therefore, mast cells and parasympathetic neurons cooperate to form a vicious circle that amplifies the bronchial constriction of choline. Asthma gets worse as the result. Why are mast cells involved in parasympathetic regulation of ASMs? Why the parasympathetic nerve manipulates mast cells to enhance its control on ASMs? Is it the result of the body’s rapid response to foreign substances? Studies showed that the interference of mast cells in ASMs occur with the development of ASMs. Following allergen exposure during early-life, mast cells in lung can produce amount of NT4, which is essential for the innervation of ASMs during development (34), causing long-term airway dysfunction. Mast cells can also produce transforming growth factor β (TGF-β) to induce β2-adrenergic receptor (β₂-AR) phosphorylation in ASMs, thereby reducing the airway dilation effect of β₂-AR agonists (35) ( Figure 1 ). Therefore, during the occurrence of allergic asthma, mast cells are activated by immunity and affect ASMs under nerve regulation, resulting in persistent airway contraction and AHR. Obviously, mast cells are closely related to the nervous system. Mast cells seem to control the distribution and function of nerves. Besides inflammatory factors, are mast cells also regulated by neurotransmitters? After all, signals travel much faster in nerves. More research is expected.

Eosinophil is accepted as an important kind of effector cells in the development of allergic asthma. Extensive eosinophil infiltration around the airway is considered a hallmark of allergic asthma (36–38). However, growing evidence suggests that eosinophils are inextricably linked to the nervous system during the development of asthma. Tropomyosin receptor kinase A is a high affinity receptor for nerve growth factor (NGF). In a tropomyosin receptor kinase A-knock-in mouse model, eosinophils are found to migrate to airway during inflammation via eotaxin-1 (39). Moreover, eosinophils are closely related to nerve fibers in asthma (40, 41). Under the action of VLA-4 and CD11b, eosinophils adhere to VCAM-1 and ICAM-1 on parasympathetic fibers (41) ( Figure 1 ). It was found that in guinea pigs (42) and monkeys (43) during allergy, eosinophil binding to VCAM-1 or ICAM-1 is important in airway hyperreactivity. Eosinophils are then activated and release major basic protein (MBP), which is an antagonist of M2 muscarinic receptor in human, thus enhancing parasympathetic mediated bronchoconstriction (40) ( Figure 1 ). Besides, airway and peripheral blood eosinophils are associated with increased airway innervation in asthma patients. Eosinophils increase airway sensory innervation in mice and humans, which is remarkable in moderate persistent asthma, thus leading to AHR (44). Strikingly, a novel study suggests that eosinophils play a much more interesting role in neuro-immune regulation than we previously have known. Eosinophil extracellular traps (EETs) are web-like DNA traps generated from eosinophils ( Figure 1 ). In asthma tissues from human and mice, PNECs are surrounded by EETs and activated via the CCDC25–ILK–PKCα–CRTC1 pathway (45). It appears that PNECs are one type of the target cells of eosinophils, but previous studies have shown that eosinophils are influenced by cells such as PNECs (46). Such interactive network regulation is not unusual for sophisticated organisms like mammals, and suggests that we need to take a dialectical view of disease.

ILC2s are important players in both neural and immune regulation. They play a vital role in asthma by releasing type 2 cytokines. Besides respond to alarmins IL-25, IL-33 and TSLP which are released by epithelium, ILC2s could also be regulated by other stimuli. ILC2s are bidirectional regulated by the nervous system ( Figure 1 ). In vitro, Nmur1 is highly expressed in ILC2s purified from mice, and neuropeptides neuromedin U (NMU) activate ILC2s by interacting with NMUR (18, 47, 48). In house dust induced airway inflammation model, NUM amplifies allergic inflammation with the combination of IL-25 (18). Vasoactive intestinal peptide (VIP) is another neuropeptide that belongs to non-adrenergic, non-cholinergic (NANC) system. VIP is one of the most potent endogenous bronchodilators and is proposed to have anti-inflammatory effects (49). However, recent study find it expressed at high levels in nodose ganglion neurons in the lung and has a positive stimulating effect on ILC2. Under the stimulation of IL-5 and OVA, the generation of VIP increase in nodose ganglion neurons both in vitro and in vivo. VIP may promote ILC2s activation partly by VIP-VPAC2 axis thus amplify the airway inflammatory (50). ILC2s are found resided in proximity to PNECs in naïve mice, and when cultured with CGRP and IL-33, ILC2s are activated with increased IL-5 production (46). However, another study analyzed single-cell RNA-seq atlas of lung ILCs and found that ILC2s express both CGRP and its encoding genes, and endogenous CGRP derived from neurons and neuroendocrine cells could negatively regulate IL-33 or IL-25 driven pulmonary ILC2s response, inhibit the production of ILC2-derived type 2 cytokines, thus reduce tissue damage under certain conditions (19). In a study of Nippostrongylus brasiliensis infection mouse model also showed that a subset of ILC2s in lung express CGRP receptor components, and CGRP limits ILC2s response and worm clearance (51). This suggests the complexity of CGRP function and ILC2s microenvironment in different disease models. Many neuro-derived factors can inhibit type 2 immune responses mediated by ILC2s. β₂-AR is an important member of the adrenergic nervous system. β₂-AR gene is detected in murine and human ILC2s. In N. brasiliensis and Alternaria alternata induced murine lung inflammation models, ILC-deficient mice exhibit increased levels of ILC2s in the lung after infection, which could be inhibited by β₂-AR agonist treatment (52). β₂-AR agonist is an important class of medicine in the treatment of asthma. It can reduce bronchial constriction by targeting β₂-AR on ASMs. Whether β₂-AR signaling also alleviate asthma symptoms by dampening ILC2 responses needs further study. α7-nicotinic acetylcholine receptor (α7nAChR) is thought to have anti-inflammatory effect in inflammatory diseases (53). α7nAChR is found expressed on murine ILC2s and α7nAChR agonist inhibited ILC2s function with decreased IL-5 and IL-13 production in vitro. By giving intranasal recombinant mouse IL-33 to Rag2-deficient mice (devoid of T and B cells), ILC2s are induced and a7nAChR agonist treatment could ameliorate ILC2s-mediated AHR by decreasing the expression of GATA-3, a key transcription factor of ILC2s (54). In conclusion, ILC2s express a variety of neuropeptide receptors. As the innate immune cells in the lung, ILC2s become the pivot of lung neuro-immune regulation.

We know that there are other types of innate immune cells, like macrophages, basophils and neutrophils. A special group of macrophages have been found near the large bronchi and airway nerves, named nerve-and airway-associated macrophages (55). This kind of macrophages can activate neurons to produce colony stimulating factor 1 (CSF1) by producing bone morphogenic protein 2, and CSF1 is the necessary signal to maintain its survival. So, nerve fibers provide nutrients for the survival of macrophages. But researches on their relationship with nervous system is still insufficient.

As we mentioned above, large numbers of Th2 cells is a hallmark of Type 2-high asthma. Th2 cells, induced and activated in lymph nodes by DCs in an antigen specific manner, produce large amounts of type 2 cytokines thus activate further immune cascades. Stimulated by Th2 cells, B cells mature into plasma cells and secrete IgE in response to cytokines IL-4 and IL-13 (56). IgE interacts with cells that have receptors FcϵRI and CD23, such as mast cells, basophils, DCs and ASMs, causing acute allergic response and AHR (3, 57).

Differentiation of T cells into Th2 cells is a landmark in the development of allergic asthma, and the subsequent production of large amounts of type 2 cytokines cause persistent inflammatory changes. These are also important molecular indicators for determining asthma severity and evaluating the effectiveness of interventions in various studies. T cells are certainly an important battleground for the nervous system to participate in immune regulation. As a transient receptor potential ankyrin channel, transient receptor potential ankyrin 1 (TRPA1) is widely expressed in sensory neurons. It can be triggered by wide variety of stimuli and release amounts of inflammatory neuropeptides and neurotransmitters, facilitating the communication between the nervous system and the immune system (58). Furthermore, adaptive immune cells may directly participate in the battlefield of neuroimmune response through TRPA1. The expression of TRPA1 is increased in lung tissues and CD4⁺ T cells in an OVA-induced mouse model of asthma, accompanied with the development and exacerbation of asthma (59). It provides a complement to non-neural sources of TRPA1. As we have discussed before, the neurotransmitter VIP regulates the immune system by acting on its receptor VPAC2. With the help of VPAC2 expressed on T cells, VIP promotes the differentiation of CD4⁺ T cells into Th2 cells and increase the production of IL-5 and IL-13 correspondingly (50). NGF has been suggested to play an important role in neuro-immune regulation in airway inflammation by overwhelming studies (60–62). The aggravating role of NGF in lung inflammation can be explained partly by regulating T and B cells. NGF exacerbates inflammation and airway remodeling by enhancing Th2 in OVA sensitized asthma in rat model (63). Suppression of NGF could reduce Th2 immune response, decrease inflammatory infiltration and airway response in murine asthma model (64). The above effects in lung inflammation resulting from inhibition of NGF is also observed in mice infected with respiratory syncytial virus (RSV) (65). And RSV infection in infants is considered a risk factor for the development of asthma (66, 67). It seems that NGF is a broad and powerful molecule involved in neuroimmune inflammation. It is worth noting that the regulation of adaptive immunity by the nervous system may partly explain the higher incidence of allergic asthma in children. It is found that during postnatal development in mice and humans, sympathetic nerves in the lung in mice and humans undergo a transition from dopaminergic type to adrenergic type. In this process, dopamine is bound to a specific dopamine receptor, DRD4, then IL-2-STAT5 signaling is upregulated and histone trimethylation is induced at Th2 gene loci, as a result, differentiation of CD4⁺ T cell to Th2 cell is promoted (68). Thus, the dopamine-DRD4 pathway augments Th2 inflammation in the lung of young mice in allergen exposure models, which is not so evident in the lungs of adult mice dominated by the adrenergic type.

NGF can also affect the function of plasma cells in the development of asthma. In a mouse model of OVA induced allergic asthma, plasma cells from airways and spleen express different patterns of neurotrophins receptors, and TrkA is only expressed on pulmonary plasma cells. In vitro, NGF promotes survival of pulmonary plasma cells by increasing transcription factors in plasma cells (X-box binding protein 1 and NF-κB subunit RelA) responsible for production of immunoglobulins. Consistently, anti-NGF treatment reduce the number of pulmonary plasma cells and serum IgE (69). B cell activation and subsequent production of large amounts of antigen-specific IgE are known to be characteristic of allergic asthma. However, studies on neural regulation on B cells or plasma cells in asthma are handful and years in advance. Interestingly and excitingly, FcϵR1, a high-affinity IgE receptor, is found expressed on vagal nociceptor neurons in lung in an OVA sensitized mouse model. It means that this kind of neurons can sense invading allergens directly, inducing allergic inflammation (70). This finding is an important addition to the understanding of neuro-immune regulation in the development of asthma, and more research is expected.