RESUMEN
A chemogenetic screen reveals links between nociceptors and gut immune function.
Asunto(s)
Microbioma Gastrointestinal , Tracto Gastrointestinal , Nociceptores , Linfocitos T Reguladores , Canales Catiónicos TRPV , Animales , Humanos , Ratones , Microbioma Gastrointestinal/inmunología , Tracto Gastrointestinal/inmunología , Nociceptores/fisiología , Nociceptores/inmunología , Ganglios Espinales/inmunología , Ganglios Espinales/fisiopatología , Linfocitos T Reguladores/inmunología , Canales Catiónicos TRPV/metabolismoRESUMEN
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.
Asunto(s)
Nociceptores , Rinitis Alérgica , Humanos , Nociceptores/metabolismo , Nociceptores/inmunología , Rinitis Alérgica/inmunología , Rinitis Alérgica/metabolismo , Animales , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Mucosa Nasal/inervación , Neuroinmunomodulación , Neuropéptidos/metabolismo , Neuropéptidos/inmunologíaAsunto(s)
Inmunidad Humoral , Nociceptores , Animales , Humanos , Nociceptores/inmunología , Nociceptores/metabolismo , RatonesRESUMEN
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.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Interleucina-23/biosíntesis , Neuroinmunomodulación/fisiología , Nociceptores/metabolismo , Psoriasis/inmunología , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos BALB C , Nociceptores/inmunología , Psoriasis/metabolismo , Receptores de Antígenos de Linfocitos T gamma-deltaAsunto(s)
Citocinas/metabolismo , Sistema Inmunológico/metabolismo , Neuroinmunomodulación , Nociceptores/metabolismo , Umbral del Dolor , Dolor/metabolismo , Animales , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiopatología , Nociceptores/inmunología , Dolor/inmunología , Dolor/fisiopatología , Transducción de SeñalRESUMEN
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.
Asunto(s)
Dolor Agudo/inmunología , Dolor Crónico/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Dolor Agudo/patología , Animales , Dolor Crónico/patología , Modelos Animales de Enfermedad , Humanos , Neuroglía/citología , Neuroglía/inmunología , Neuroglía/patología , Enfermedades Neuroinflamatorias/patología , Nociceptores/inmunología , Nociceptores/metabolismo , Receptores de Interferón/metabolismo , Transducción de Señal/inmunología , Médula Espinal/citología , Médula Espinal/inmunología , Médula Espinal/patologíaRESUMEN
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.
Asunto(s)
Fibromialgia/inmunología , Fibromialgia/fisiopatología , Animales , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Fibromialgia/etiología , Ganglios Espinales/fisiopatología , Humanos , Inmunización Pasiva , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Nociceptores/inmunología , Nociceptores/fisiología , Dolor/fisiopatología , Umbral del Dolor/fisiologíaRESUMEN
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.
Asunto(s)
Analgesia/efectos adversos , Ejercicio Físico , Músculo Esquelético/patología , Nociceptores/patología , Estrés Oxidativo , Dolor/patología , Células Receptoras Sensoriales/patología , Humanos , Músculo Esquelético/metabolismo , Nociceptores/inmunología , Nociceptores/metabolismo , Oxidación-Reducción , Dolor/etiología , Dolor/metabolismo , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/metabolismoRESUMEN
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.
Asunto(s)
Citocinas/inmunología , Mediadores de Inflamación/inmunología , Neuralgia/inmunología , Neuroinmunomodulación/inmunología , Células Receptoras Sensoriales/inmunología , Piel/inmunología , Animales , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Modelos Inmunológicos , Neuralgia/metabolismo , Neuralgia/fisiopatología , Nociceptores/inmunología , Nociceptores/metabolismo , Células Receptoras Sensoriales/metabolismo , Piel/inervación , Piel/metabolismoRESUMEN
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.
Asunto(s)
Interacciones Microbiota-Huesped/fisiología , Interacciones Huésped-Patógeno/fisiología , Nociceptores , Zinc/metabolismo , Animales , Nociceptores/inmunología , Nociceptores/microbiologíaRESUMEN
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.
Asunto(s)
Envejecimiento/inmunología , COVID-19/inmunología , Inmunidad Innata/inmunología , Pulmón/inmunología , Nociceptores/inmunología , SARS-CoV-2/inmunología , Canales de Potencial de Receptor Transitorio/inmunología , Anciano , COVID-19/virología , Humanos , Pulmón/inervación , Pulmón/virología , Nociceptores/metabolismo , Nociceptores/virología , SARS-CoV-2/fisiología , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/virología , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
BACKGROUND & AIMS: Despite achieving endoscopic remission, more than 20% of inflammatory bowel disease patients experience chronic abdominal pain. These patients have increased rectal transient receptor potential vanilloid-1 receptor (TRPV1) expression, a key transducer of inflammatory pain. Because inflammatory bowel disease patients in remission exhibit dysbiosis and microbial manipulation alters TRPV1 function, our goal was to examine whether microbial perturbation modulated transient receptor potential function in a mouse model. METHODS: Mice were given dextran sodium sulfate (DSS) to induce colitis and were allowed to recover. The microbiome was perturbed by using antibiotics as well as fecal microbial transplant (FMT). Visceral and somatic sensitivity were assessed by recording visceromotor responses to colorectal distention and using hot plate/automated Von Frey tests, respectively. Calcium imaging of isolated dorsal root ganglia neurons was used as an in vitro correlate of nociception. The microbiome composition was evaluated via 16S rRNA gene variable region V4 amplicon sequencing, whereas fecal short-chain fatty acids (SCFAs) were assessed by using targeted mass spectrometry. RESULTS: Postinflammatory DSS mice developed visceral and somatic hyperalgesia. Antibiotic administration during DSS recovery induced visceral, but not somatic, hyperalgesia independent of inflammation. FMT of postinflammatory DSS stool into antibiotic-treated mice increased visceral hypersensitivity, whereas FMT of control stool reversed antibiotics' sensitizing effects. Postinflammatory mice exhibited both increased SCFA-producing species and fecal acetate/butyrate content compared with controls. Capsaicin-evoked calcium responses were increased in naive dorsal root ganglion neurons incubated with both sodium butyrate/propionate alone and with colonic supernatants derived from postinflammatory mice. CONCLUSIONS: The microbiome plays a central role in postinflammatory visceral hypersensitivity. Microbial-derived SCFAs can sensitize nociceptive neurons and may contribute to the pathogenesis of postinflammatory visceral pain.
Asunto(s)
Colitis Ulcerosa/complicaciones , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Dolor Visceral/inmunología , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Colon/efectos de los fármacos , Colon/inmunología , Colon/microbiología , Colon/patología , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Disbiosis/microbiología , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Heces/química , Heces/microbiología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones , Nocicepción , Nociceptores/inmunología , Nociceptores/metabolismo , Canales Catiónicos TRPV/metabolismo , Dolor Visceral/microbiologíaRESUMEN
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.
Asunto(s)
Citrobacter rodentium/inmunología , Sistema Nervioso Entérico/inmunología , Infecciones por Enterobacteriaceae/inmunología , Interacciones Huésped-Patógeno/inmunología , Nociceptores/inmunología , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/citología , Sistema Nervioso Entérico/efectos de los fármacos , Infecciones por Enterobacteriaceae/microbiología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Mucosa Intestinal/inervación , Mucosa Intestinal/microbiología , Intestino Delgado/inervación , Intestino Delgado/microbiología , Ratones , Ratones Noqueados , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Canales Catiónicos TRPV/genéticaRESUMEN
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.
Asunto(s)
Alérgenos/inmunología , Dermatitis Atópica/inmunología , Mastocitos/inmunología , Nociceptores/inmunología , Pyroglyphidae/inmunología , Animales , Comunicación Celular/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Mastocitos/metabolismo , Ratones Noqueados , Nociceptores/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Piel/citología , Piel/inmunología , Canales Catiónicos TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismoRESUMEN
Increasing evidence suggests that nerve fibers responding to noxious stimuli (nociceptors) modulate immunity in a variety of tissues, including the skin. Yet, the role of nociceptors in regulating sterile cutaneous inflammation remains unexplored. To address this question, we have developed a detailed description of the sterile inflammation caused by overexposure to UVB irradiation (i.e., sunburn) in the mouse plantar skin. Using this model, we observed that chemical depletion of nociceptor terminals did not alter the early phase of the inflammatory response to UVB, but it caused a significant increase in the number of dendritic cells and αß+ T cells as well as enhanced extravasation during the later stages of inflammation. Finally, we showed that such regulation was driven by the nociceptive neuropeptide calcitonin gene-related peptide. In conclusion, we propose that nociceptors not only play a crucial role in inflammation through avoidance reflexes and behaviors, but can also regulate sterile cutaneous immunity in vivo.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Dermatitis/inmunología , Nociceptores/inmunología , Piel/efectos de la radiación , Quemadura Solar/inmunología , Animales , Péptido Relacionado con Gen de Calcitonina/genética , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Diterpenos/toxicidad , Femenino , Humanos , Ratones , Ratones Noqueados , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/inmunología , Fibras Nerviosas/metabolismo , Neurotoxinas/toxicidad , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Piel/citología , Piel/inmunología , Piel/inervación , Canal Catiónico TRPA1/genética , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Rayos Ultravioleta/efectos adversosRESUMEN
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.
Asunto(s)
Ácidos y Sales Biliares/toxicidad , Hipersensibilidad/patología , Síndrome del Colon Irritable/patología , Mastocitos/inmunología , Factor de Crecimiento Nervioso/metabolismo , Nociceptores/inmunología , Receptores Citoplasmáticos y Nucleares/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Animales , Estudios de Casos y Controles , Células Cultivadas , Femenino , Fármacos Gastrointestinales/toxicidad , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Síndrome del Colon Irritable/inducido químicamente , Síndrome del Colon Irritable/metabolismo , Masculino , Mastocitos/metabolismo , Mastocitos/patología , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Nociceptores/metabolismo , Nociceptores/patología , Ratas , Ratas Sprague-Dawley , Dolor Visceral/inducido químicamente , Dolor Visceral/metabolismo , Dolor Visceral/patologíaRESUMEN
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.
Asunto(s)
Mediadores de Inflamación/inmunología , Interleucina-1/inmunología , Mastocitos/inmunología , Humanos , Inflamación/inmunología , Inflamación/patología , Mastocitos/patología , Neuroglía/inmunología , Neuroglía/patología , Neuronas/inmunología , Neuronas/patología , Nociceptores/inmunología , Nociceptores/patologíaRESUMEN
Candida albicans can enter skeletal tissue through a skin wound in an immunocompromised host or by contamination during orthopedic surgery. Such Candida osteomyelitis is accompanied by severe pain and bone destruction. It is established that nociceptor innervation occurs in skin and bone, but the mechanisms of nociceptive modulation in fungal inflammation remain unclear. In this study, we show that C. albicans stimulates Nav1.8-positive nociceptors via the ß-glucan receptor Dectin-1 to induce calcitonin gene-related peptide (CGRP). This induction of CGRP is independent of Bcl-10 or Malt-1 but dependent on transient receptor potential cation channel subfamily V member 1 (TRPV1)/transient receptor potential cation channel subfamily A member 1 (TRPA1) ion channels. Hindpaw ß-glucan injection after Nav1.8-positive nociceptor ablation or in TRPV1/TRPA1 deficiency showed dramatically increased osteoinflammation accompanied by impaired CGRP production. Strikingly, CGRP suppressed ß-glucan-induced inflammation and osteoclast multinucleation via direct suppression of nuclear factor-κB (NF-κB) p65 by the transcriptional repressor Jdp2 and inhibition of actin polymerization, respectively. These findings clearly suggest a role for Dectin-1-mediated sensocrine pathways in the resolution of fungal osteoinflammation.
Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Inflamación/inmunología , Nociceptores/inmunología , Proteínas Represoras/inmunología , Canales Catiónicos TRPV/inmunología , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Candidiasis/metabolismo , Candidiasis/patología , Femenino , Humanos , Inflamación/microbiología , Ratones , Proteínas Represoras/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.
Asunto(s)
Dolor Crónico/fisiopatología , Neuritis/fisiopatología , Nociceptores/fisiología , Dolor/fisiopatología , Animales , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/fisiopatología , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/etiología , Ganglios Espinales/fisiopatología , Humanos , Queratinocitos/fisiología , Macrófagos/fisiología , Ratones , Monocitos/fisiología , Neoplasias/fisiopatología , Neuritis/complicaciones , Neuritis/tratamiento farmacológico , Neuroglía/fisiología , Nociceptores/inmunología , Ratas , Médula Espinal/fisiopatología , Linfocitos T/fisiología , Receptores Toll-Like/fisiologíaRESUMEN
Prostaglandin E2 (PGE2) is one of the major signaling molecules involved in hyperalgesia, acting directly on nociceptors and resulting in the activation of PKA and PKC. Once active, these kinases phosphorylate many cellular proteins, resulting in changes on nociceptors sensorial transduction properties. The Janus Kinases (JAKs) are a family of intracellular signaling molecules generally associated with cytokine signaling, and their activity can be increased in nociceptors after peripheral inflammation. However, there are no evidences of JAKs direct involvement in PGE2 mediated sensitization of nociceptors. Therefore, the aim of the present study was to explore a possible role for JAKs in PGE2 mediated sensitization. In cultured dorsal root ganglion (DRG) neurons, we observed that the administration of PGE2 increases capsaicin induced calcium transients, and a pre-incubation of DRG cells with the JAK inhibitor AG490 blocks this PGE2 in vitro effect. Intrathecal administration of AG490 to ten-weeks-old male Wistar rats reduces the hyperalgesia induced by the intraplantar administration of PGE2 or carrageenan in the right hind paw. We also observed that carrageenan administration in the right hind paw induced an increase in membrane associated PKCepsilon in the ipsilateral L5 DRG, and this increase was blocked by intrathecal AG490 administration. In conclusion the present study indicates that the JAKs expressed in the DRG and spinal cord may have a role in the sensitization of nociceptors by a peripheral inflammatory event. Moreover, the inhibition of JAKs may be a possible novel pharmacological target for the control of the inflammatory hyperalgesia.