House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation.

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

Setting the tone: nociceptors as conductors of immune responses.

Nociceptors have emerged as master regulators of immune responses in both homeostatic and pathologic settings; however, their seemingly contradictory effects on the functions of different immune cell subsets have been a source of confusion. Nevertheless, work by many groups in recent years has begun to identify patterns of the modalities and consequences of nociceptor-immune system communication. Here, we review recent findings of how nociceptors affect immunity and propose an integrated concept whereby nociceptors are neither inherently pro- nor anti-inflammatory. Rather, we propose that nociceptors have the role of a rheostat that, in a context-dependent manner, favors tissue homeostasis and fine-tunes immunity by preventing excessive histotoxic inflammation, promoting tissue repair, and potentiating anticipatory and adaptive immune responses.

Zinc is an important inter-kingdom signal between the host and microbe.

Zinc (Zn) is an essential trace element in living organisms and plays a vital role in the regulation of both microbial virulence and host immune responses. A growing number of studies have shown that zinc deficiency or the internal Zn concentration does not meet the needs of animals and microbes, leading to an imbalance in zinc homeostasis and intracellular signalling pathway dysregulation. Competition for zinc ions (Zn2+) between microbes and the host exists in the use of Zn2+ to maintain cell structure and physiological functions. It also affects the interplay between microbial virulence factors and their specific receptors in the host. This review will focus on the role of Zn in the crosstalk between the host and microbe, especially for changes in microbial pathogenesis and nociceptive neuron-immune interactions, as it may lead to new ways to prevent or treat microbial infections.

Sensory Nociceptive Neurons Contribute to Host Protection During Enteric Infection With Citrobacter rodentium.

BACKGROUND: Neurons are an integral component of the immune system that functions to coordinate responses to bacterial pathogens. Sensory nociceptive neurons that can detect bacterial pathogens are found throughout the body with dense innervation of the intestinal tract. METHODS: In this study, we assessed the role of these nerves in the coordination of host defenses to Citrobacter rodentium. Selective ablation of nociceptive neurons significantly increased bacterial burden 10 days postinfection and delayed pathogen clearance. RESULTS: Because the sensory neuropeptide CGRP (calcitonin gene-related peptide) regulates host responses during infection of the skin, lung, and small intestine, we assessed the role of CGRP receptor signaling during C rodentium infection. Although CGRP receptor blockade reduced certain proinflammatory gene expression, bacterial burden and Il-22 expression was unaffected. CONCLUSIONS: Our data highlight that sensory nociceptive neurons exert a significant host protective role during C rodentium infection, independent of CGRP receptor signaling.

Crosstalk between the nociceptive and immune systems in host defence and disease.

Nociceptors and immune cells both protect the host from potential threats to homeostasis. There is growing evidence for bidirectional signalling between these two systems, and the underlying mechanisms are beginning to be elucidated. An understanding is emerging of how both the adaptive and innate immune systems can activate and sensitize nociceptors, and, reciprocally, how nociceptors modulate immune cells. In this Review, we discuss how these interactions can be adaptive and useful to the organism but also consider when such signalling might be maladaptive and pathophysiological, contributing to immune-mediated diseases and persistent pain states.

Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.

Increased colonic bile acid (BA) exposure, frequent in diarrhea-predominant irritable bowel syndrome (IBS-D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hypersensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)-to-nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC-derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti-NGF treatment and TRPV1 antagonism inhibited BA-induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS-D with elevated colonic BA content transcriptionally induced NGF expression. In FXR-/- mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA-induced NGF expression and release in mast cells. Mitogen-activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF-κB signaling was mechanistically responsible for FXR-mediated NGF expression and secretion. The findings show an MMC-dependent and FXR-mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC-to-neuron communication during pain processing in IBS.-Li, W.-T., Luo, Q.-Q., Wang, B., Chen, X., Yan, X.-J., Qiu, H.-Y., Chen, S.-L. Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.

New concepts in neuroinflammation: mast cells pro-inflammatory and anti-inflammatory cytokine mediators.

The activation of brain nociceptors and neurons may lead to neurogenic inflammation, an event that involves immune cells including mast cells (MCs). Microglia are similar to macrophages and secrete pro-inflammatory IL-1 family members and TNF. TNF is rapidly released (first 10 minutes from MC granules) and is subsequently secreted along with other pro-inflammatory cytokines with a new synthesis after several hours. MC-derived TNF is a very powerful pro-inflammatory cytokine which mediates sensitization of the meningeal nociceptors. Here, we report the involvement of MCs in neuroinflammation, the role of inflammatory cytokine IL-1 family members, and of TNF, as well as the potential inhibition of IL-37.

Peripheral Nociceptors as Immune Sensors in the Development of Pain and Itch.

The peripheral nervous system and the immune system perform a series of similar functionalities such as recognizing, responding, and adapting to external or internal stimuli despite significant morphological differences. The peripheral nervous system actively communicates and coordinates with the immune system to function as a unified defense system. The peripheral nervous system is highly regulated by the immune system, especially under inflammatory conditions. On the other hand, the nervous system can modulate the immune system via neurotransmitters and chemokines released by the peripheral nerve endings, particularly from nociceptors. In both physiological and pathological conditions, peripheral nociceptive (including pruriceptive) neurons may express a variety of immune-related receptors, such as chemokine receptors and immunoglobulin (Fc) receptors that are usually found on immune cells. Certain ligands such as chemokines and immune complexes may induce abnormal neuronal hyperexcitability and even ectopic action potential discharges, therefore producing the sensation of pain and/or itch in immune-related diseases. The immune-sensing mechanisms of peripheral nociceptors may play an important role in the development of chronic pain and pruritus and may indicate novel therapeutic strategies for these pathological conditions.

Adapting to environmental stresses: the role of the microbiota in controlling innate immunity and behavioral responses.

Mammals are subject to colonization by an astronomical number of mutualistic and commensal microorganisms on their environmental exposed surfaces. These mutualistic species build up a complex community, called the indigenous microbiota, which aid their hosts in several physiological activities. In this review, we show that the transition between a non-colonized and a colonized state is associated with modification on the pattern of host inflammatory and behavioral responsiveness. There is a shift from innate anti-inflammatory cytokine production to efficient release of proinflammatory mediators and rapid mobilization of leukocytes upon infection or other stimuli. In addition, host responses to hypernociceptive and stressful stimuli are modulated by indigenous microbiota, partly due to the altered pattern of innate and acquired immune responsiveness of the non-colonized host. These altered responses ultimately lead to significant alteration in host behavior to environmental threats. Therefore, host colonization by indigenous microbiota modifies the way the host perceives and reacts to environmental stimuli, improving resilience of the entire host-microorganism consortium to environmental stresses.

Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice.

RATIONALE: Airway hyperreactivity (AHR) is a key feature of bronchial asthma, and inhalation of irritants may facilitate development of nonallergic AHR. Swimmers exposed to hypochlorite (ClO(-))-containing water show a higher risk of developing AHR. We developed a mouse model in which instillation of ClO(-) before ovalbumin (OVA) induces AHR without bronchial inflammatory cells. OBJECTIVES: To investigate the mechanisms of ClO(-)-OVA-induced nonallergic AHR. METHODS: The involvement of the transient receptor potential ankyrin (TRPA)1 channel was checked in vivo by the use of TRPA1(-/-) mice and in vitro by Ca(2+) imaging experiments. The role of substance P (SP) was investigated by pretreating animals with the receptor antagonist RP67580, by replacing ClO(-) with SP in vivo, and by immunofluorescent staining of large airways of exposed mice. The role of mast cells was evaluated by exposing mast cell-deficient Kit(Wh)/Kit(Wsh) mice to ClO(-)-OVA with or without mast cell reconstitution. MEASUREMENTS AND MAIN RESULTS: ClO(-)-OVA did not induce AHR in TRPA1(-/-) mice, and ClO(-) generates a Ca(2+) influx in TRPA1-transfected cells. Pretreatment with RP67580 reduces ClO(-)-OVA-induced AHR, although no increased SP expression was shown in the airways. SP-OVA exposure resulted in the same AHR as induced by ClO(-)-OVA. Kit(Wsh)/Kit(Wsh) mice did not develop AHR in response to ClO(-)-OVA unless they were reconstituted with bone marrow-derived mast cells. CONCLUSIONS: Induction of AHR by exposure to ClO(-)-OVA depends on a neuroimmune interaction that involves TRPA1-dependent stimulation of sensory neurons and mast cell activation.

The role of nociceptive neurons in allergic rhinitis.

Allergic rhinitis (AR) is a chronic, non-infectious condition affecting the nasal mucosa, primarily mediated mainly by IgE. Recent studies reveal that AR is intricately associated not only with type 2 immunity but also with neuroimmunity. Nociceptive neurons, a subset of primary sensory neurons, are pivotal in detecting external nociceptive stimuli and modulating immune responses. This review examines nociceptive neuron receptors and elucidates how neuropeptides released by these neurons impact the immune system. Additionally, we summarize the role of immune cells and inflammatory mediators on nociceptive neurons. A comprehensive understanding of the dynamic interplay between nociceptive neurons and the immune system augments our understanding of the neuroimmune mechanisms underlying AR, thereby opening novel avenues for AR treatment modalities.

Mapping gut feelings and immune control.

A chemogenetic screen reveals links between nociceptors and gut immune function.

Local action of the proinflammatory cytokines IL-1ß and IL-6 on intracranial meningeal nociceptors.

BACKGROUND: Peripheral nociceptive action of the proinflammatory cytokines IL-1ß and IL-6 has been implicated in the pathogenesis of numerous pain syndromes. An increase in the level of these cytokines in jugular venous blood has been reported during migraine attacks, suggesting their potential involvement in mediating the intracranial headache of migraine. METHODS: In this work we examined, using in vivo single-unit recording of meningeal nociceptors in the trigeminal ganglion of anesthetized rats, whether the peripheral actions of IL-1ß and IL-6 can promote the activation and sensitization of nociceptors that innervate the intracranial meninges, two neural processes that are believed to play a key role in promoting the intracranial throbbing pain of migraine. RESULTS: We found that meningeal application of IL-1ß leads to the activation and mechanical sensitization of about 70% and 45% of the nociceptors respectively. In contrast, IL-6 was a very poor modulator of meningeal nociceptors' response properties affecting overall only about 20% of the nociceptors. CONCLUSIONS: Our study provides for the first time in vivo electrophysiological evidence that meningeal action of IL-1ß can promote the activation and increased mechanosensitivity of intracranial meningeal nociceptors and that IL-6 generally lacks these properties. Future studies are required to examine the mechanism that plays a role in mediating the nociceptive effects of IL-1ß on meningeal nociceptors, which may serve as a target for migraine therapy.

Nociceptive Sensory Fibers Drive Interleukin-23 Production in a Murine Model of Psoriasis via Calcitonin Gene-Related Peptide.

Neuroimmunity is involved in the pathogenesis of psoriasis, but the mechanism underlying the interaction between the nervous system and the interleukin (IL)-23/IL-17 immune axis is yet unclear. This study reveals the essential role of the sensory neuron-derived calcitonin gene-related peptide (CGRP) in imiquimod (IMQ)-induced expression of IL-23. First, we show that the increased nociceptive behavior was consistent with the development of psoriasiform dermatitis, which requires intact sensory innervation. Systemic ultrapotent Transient receptor potential vanilloid 1 (TRPV1) agonist (resiniferatoxin, RTX) treatment-induced sensory denervation resulted in a significant decrease in IL-23 expression in this model, while the recombinant IL-23 treatment induced IL-17A expression was intact after RTX treatment. In addition, IMQ exposure induced a transient increase in CGRP expression in the dorsal root ganglion. The neuron-derived CGRP expression was completely abolished by sensory denervation, thereby downregulating IL-23 expression, which could be reversed through the introduction of CGRP into the denervated dorsal skin. Our results suggest that nociceptive sensory neurons may drive the production of IL-23, resulting in IL-17A production from γδ T cells via the neuropeptide CGRP in the pathology of psoriasis.

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States.

Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.

Redox interactions of immune cells and muscle in the regulation of exercise-induced pain and analgesia: implications on the modulation of muscle nociceptor sensory neurons.

The mechanistic interactions among redox status of leukocytes, muscle, and exercise in pain regulation are still poorly understood and limit targeted treatment. Exercise benefits are numerous, including the treatment of chronic pain. However, unaccustomed exercise may be reported as undesirable as it may contribute to pain. The aim of the present review is to evaluate the relationship between oxidative metabolism and acute exercise-induced pain, and as to whether improved antioxidant capacity underpins the analgesic effects of regular exercise. Preclinical and clinical studies addressing relevant topics on mechanisms by which exercise modulates the nociceptive activity and how redox status can outline pain and analgesia are discussed, in sense of translating into refined outcomes. Emerging evidence points to the role of oxidative stress-induced signaling in sensitizing nociceptor sensory neurons. In response to acute exercise, there is an increase in oxidative metabolism, and consequently, pain. Instead, regular exercise can modulate redox status in favor of antioxidant capacity and repair mechanisms, which have consequently increased resistance to oxidative stress, damage, and pain. Data indicate that acute sessions of unaccustomed prolonged and/or intense exercise increase oxidative metabolism and regulate exercise-induced pain in the post-exercise recovery period. Further, evidence demonstrates regular exercise improves antioxidant status, indicating its therapeutic utility for chronic pain disorders. An improved comprehension of the role of redox status in exercise can provide helpful insights into immune-muscle communication during pain modulatory effects of exercise and support new therapeutic efforts and rationale for the promotion of exercise.

Passive transfer of fibromyalgia symptoms from patients to mice.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions.

Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-ß are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-ß can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.

Innate Receptors Expression by Lung Nociceptors: Impact on COVID-19 and Aging.

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.