RESUMO
Increasing evidences demonstrate the role of sensory innervation in bone metabolism, remodeling and repair, however neurovascular coupling in bone is rarely studied. Using microfluidic devices as an indirect co-culture model to mimic in vitro the physiological scenario of innervation, our group demonstrated that sensory neurons (SNs) were able to regulate the extracellular matrix remodeling by endothelial cells (ECs), in particular through sensory neuropeptides, i.e. calcitonin gene-related peptide (CGRP) and substance P (SP). Nonetheless, still little is known about the cell signaling pathways and mechanism of action in neurovascular coupling. Here, in order to characterize the communication between SNs and ECs at molecular level, we evaluated the effect of SNs and the neuropeptides CGRP and SP on ECs. We focused on different pathways known to play a role on endothelial functions: calcium signaling, p38 and Erk1/2; the control of signal propagation through Cx43; and endothelial functions through the production of nitric oxide (NO). The effect of SNs was evaluated on ECs Ca2+ influx, the expression of Cx43, endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, p38, ERK1/2 as well as their phosphorylated forms. In addition, the role of CGRP and SP were either analyzed using respective antagonists in the co-culture model, or by adding directly on the ECs monocultures. We show that capsaicin-stimulated SNs induce increased Ca2+ influx in ECs. SNs stimulate the increase of NO production in ECs, probably involving a decrease in the inhibitory eNOS T495 phosphorylation site. The neuropeptide CGRP, produced by SNs, seems to be one of the mediators of this effect in ECs since NO production is decreased in the presence of CGRP antagonist in the co-culture of ECs and SNs, and increased when ECs are stimulated with synthetic CGRP. Taken together, our results suggest that SNs play an important role in the control of the endothelial cell functions through CGRP production and NO signaling pathway.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Células Endoteliais , Óxido Nítrico , Células Receptoras Sensoriais , Transdução de Sinais , Substância P , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Substância P/farmacologia , Substância P/metabolismo , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Animais , Óxido Nítrico/metabolismo , Técnicas de Cocultura , Comunicação Celular/fisiologia , Comunicação Celular/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Células Cultivadas , Humanos , RatosRESUMO
Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6Chi monocytes and cytokine induction. Depletion of Ly6Chi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6Chi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6Chi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Carbapenêmicos , Infecções por Klebsiella , Klebsiella pneumoniae , Pulmão , Nociceptores , Sepse , Animais , Klebsiella pneumoniae/fisiologia , Camundongos , Infecções por Klebsiella/microbiologia , Sepse/metabolismo , Sepse/microbiologia , Pulmão/microbiologia , Pulmão/metabolismo , Carbapenêmicos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Nociceptores/metabolismo , Monócitos/metabolismo , Células Receptoras Sensoriais/metabolismo , Neutrófilos/metabolismo , Modelos Animais de Doenças , Antígenos Ly/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/patologia , Camundongos Endogâmicos C57BLRESUMO
Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.
Assuntos
Neoplasias Ósseas , Peptídeo Relacionado com Gene de Calcitonina , Proliferação de Células , Progressão da Doença , Células Receptoras Sensoriais , Animais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Humanos , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Receptoras Sensoriais/metabolismo , Linhagem Celular Tumoral , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/genética , Feminino , Masculino , Transdução de SinaisRESUMO
Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aß), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aß), the goal of this work was to examine Aß-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aß-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mutação , Presenilina-1 , Animais , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Quimiotaxia/genética , Modelos Animais de Doenças , Presenilina-1/genética , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologiaAssuntos
Microcirculação , Células Receptoras Sensoriais , Pele , Humanos , Microcirculação/fisiologia , Pele/irrigação sanguínea , Pele/metabolismo , Células Receptoras Sensoriais/fisiologia , Células Receptoras Sensoriais/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Animais , Complicações do Diabetes/fisiopatologiaRESUMO
Somatosensory neurons can sense external temperature by converting sensation of temperature information to neural activity via afferent input to the central nervous system. Various populations of somatosensory neurons have specialized gene expression, including expression of thermosensitive transient receptor potential (TRP) ion channels. Thermosensitive TRP channels are responsible for thermal transduction at the peripheral ends of somatosensory neurons and can sense a wide range of temperatures. Here we focus on several thermosensitive TRP channels including TRPV1, TRPV4, TRPM2, TRPM3, TRPM8, TRPC5, and TRPA1 in sensory neurons. TRPV3, TRPV4, and TRPC5 are also involved in somatosensation in nonneuronal cells and tissues. In particular, we discuss whether skin senses ambient temperatures through TRPV3 and TRPV4 activation in skin keratinocytes and the involvement of TRPM2 expressed by hypothalamic neurons in thermosensation in the brain.
Assuntos
Sensação Térmica , Canais de Potencial de Receptor Transitório , Humanos , Sensação Térmica/fisiologia , Sensação Térmica/genética , Animais , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/fisiologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Pele/metabolismo , Pele/inervação , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/genética , Queratinócitos/metabolismoRESUMO
Temperature detection is essential for the survival and perpetuation of any species. Thermoreceptors in the skin sense the body temperature and also the temperatures of the ambient air and the objects. In 1997, Dr. David Julius and his colleagues found that a receptor expressed in small-diameter primary sensory neurons was activated by capsaicin (the pungent chemical in hot pepper). This receptor was also activated by temperature above 42 °C. That was the first time that a thermal receptor in primary sensory neurons has been identified. This receptor is named transient receptor potential vanilloid 1 (TRPV1). Now, 11 thermosensitive TRP channels are known. In this chapter, we summarize the reports and analyze thermosensitive TRP channels in a variety of ways to clarify the activation mechanisms by which temperature changes are sensed.
Assuntos
Canais de Cátion TRPV , Sensação Térmica , Canais de Potencial de Receptor Transitório , Humanos , Animais , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Cátion TRPV/metabolismo , Sensação Térmica/fisiologia , Temperatura , Capsaicina/farmacologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Termorreceptores/metabolismo , Termorreceptores/fisiologiaRESUMO
Adult central nervous system (CNS) neurons down-regulate growth programs after injury, leading to persistent regeneration failure. Coordinated lipids metabolism is required to synthesize membrane components during axon regeneration. However, lipids also function as cell signaling molecules. Whether lipid signaling contributes to axon regeneration remains unclear. In this study, we showed that lipin1 orchestrates mechanistic target of rapamycin (mTOR) and STAT3 signaling pathways to determine axon regeneration. We established an mTOR-lipin1-phosphatidic acid/lysophosphatidic acid-mTOR loop that acts as a positive feedback inhibitory signaling, contributing to the persistent suppression of CNS axon regeneration following injury. In addition, lipin1 knockdown (KD) enhances corticospinal tract (CST) sprouting after unilateral pyramidotomy and promotes CST regeneration following complete spinal cord injury (SCI). Furthermore, lipin1 KD enhances sensory axon regeneration after SCI. Overall, our research reveals that lipin1 functions as a central regulator to coordinate mTOR and STAT3 signaling pathways in the CNS neurons and highlights the potential of lipin1 as a promising therapeutic target for promoting the regeneration of motor and sensory axons after SCI.
Assuntos
Axônios , Neurônios Motores , Regeneração Nervosa , Fosfatidato Fosfatase , Fator de Transcrição STAT3 , Transdução de Sinais , Traumatismos da Medula Espinal , Serina-Treonina Quinases TOR , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Animais , Axônios/metabolismo , Axônios/fisiologia , Regeneração Nervosa/fisiologia , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fosfatidato Fosfatase/metabolismo , Fosfatidato Fosfatase/genética , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Camundongos , Ácidos Fosfatídicos/metabolismo , Células Receptoras Sensoriais/metabolismo , Feminino , Tratos Piramidais/metabolismo , Tratos Piramidais/patologiaRESUMO
The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here, we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression program at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C, promoter-capture Hi-C, CUT&Tag for H3K27ac and RNA-seq. We find that genes involved in axonal regeneration form long-range, complex chromatin loops, and that cohesin is required for the full induction of the regenerative transcriptional program. Importantly, loss of cohesin results in disruption of chromatin architecture and severely impaired nerve regeneration. Complex enhancer-promoter loops are also enriched in the human fetal cortical plate, where the axonal growth potential is highest, and are lost in mature adult neurons. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent long-range promoter interactions in nerve regeneration.
Assuntos
Axônios , Cromatina , Coesinas , Regeneração Nervosa , Regiões Promotoras Genéticas , Células Receptoras Sensoriais , Animais , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Camundongos , Regiões Promotoras Genéticas/genética , Cromatina/metabolismo , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Axônios/metabolismo , Axônios/fisiologia , Humanos , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Elementos Facilitadores Genéticos/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Gânglios Espinais/metabolismo , Gânglios Espinais/citologia , Nervo Isquiático/metabolismoRESUMO
Photobiomodulation therapy (PBMT) is a form of treatment commonly used for routine clinical applications, such as wound healing of the skin and reduction of inflammation. Additionally, PBMT has been explored for its potential in pain relief. In this work, we investigated the effect of PBMT on ion content within the 50B11 sensory neurons cell line in vitro using X-Ray fluorescence (XRF) and atomic force microscope (AFM) analysis. Two irradiation protocols were selected utilizing near-infrared laser lights at 800 and 970 nm, with cell fixation immediately following irradiation. Results showed a decrease in Calcium content after irradiation with both protocols, and with lidocaine, used as an analgesic control. Furthermore, a reduction in Potassium content was observed, particularly evident when normalized to cellular volume. These findings provide valuable insights into the molecular impact of PBMT within 50B11 sensory neurons under normal conditions. Such understanding may contribute to the wider adoption of PBMT as a therapeutic approach.
Assuntos
Cálcio , Raios Infravermelhos , Terapia com Luz de Baixa Intensidade , Células Receptoras Sensoriais , Animais , Células Receptoras Sensoriais/efeitos da radiação , Células Receptoras Sensoriais/metabolismo , Cálcio/metabolismo , Camundongos , Linhagem Celular , Espectrometria por Raios X , Microscopia de Força Atômica , Potássio/metabolismo , Potássio/química , Lidocaína/farmacologiaRESUMO
Temperature detection is essential for the survival and perpetuation of any species. Thermoreceptors in the skin sense body temperature as well as the temperatures of ambient air and objects. Since Dr. David Julius and his colleagues discovered that TRPV1 is expressed in small-diameter primary sensory neurons, and activated by temperatures above 42 °C, 11 of thermo-sensitive TRP channels have been identified. TRPM3 expressed in sensory neurons acts as a sensor for noxious heat. TRPM4 and TRPM5 are Ca2âº-activated monovalent cation channels, and their activity is drastically potentiated by temperature increase. This review aims to summarize the expression patterns, electrophysiological properties, and physiological roles of TRPM3, TRPM4, and TRPM5 associated with thermosensation.
Assuntos
Canais de Cátion TRPM , Canais de Cátion TRPM/metabolismo , Animais , Humanos , Sensação Térmica/fisiologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Termorreceptores/fisiologia , Termorreceptores/metabolismoRESUMO
Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.
Assuntos
Alérgenos , Hipersensibilidade Alimentar , Neuroimunomodulação , Células Receptoras Sensoriais , Humanos , Hipersensibilidade Alimentar/imunologia , Animais , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/metabolismo , Alérgenos/imunologia , Pele/imunologiaRESUMO
BACKGROUND: Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants. METHODS: We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(-/-) and TRPV1(-/-) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo. RESULTS: Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(-/-) mouse DRG neurons but was not significant in the TRPV1(-/-) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(-/-) mice. CONCLUSIONS: These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole.
Assuntos
Antifúngicos , Cálcio , Econazol , Gânglios Espinais , Células Receptoras Sensoriais , Canal de Cátion TRPA1 , Canais de Cátion TRPV , Canais de Potencial de Receptor Transitório , Animais , Econazol/farmacologia , Canal de Cátion TRPA1/metabolismo , Canal de Cátion TRPA1/genética , Antifúngicos/toxicidade , Antifúngicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/citologia , Humanos , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/genética , Células HEK293 , Cálcio/metabolismo , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Camundongos , Masculino , Camundongos Knockout , Camundongos Endogâmicos C57BL , Prurido/induzido quimicamente , Dor/tratamento farmacológicoRESUMO
Sensory axons projecting to the central nervous system are organized into topographic maps that represent the locations of sensory stimuli. In some sensory systems, even adjacent sensory axons are arranged topographically, forming "fine-scale" topographic maps. Although several broad molecular gradients are known to instruct coarse topography, we know little about the molecular signaling that regulates fine-scale topography at the level of two adjacent axons. Here, we provide evidence that transsynaptic bone morphogenetic protein (BMP) signaling mediates local interneuronal communication to regulate fine-scale topography in the nociceptive system of Drosophila larvae. We first show that the topographic separation of the axon terminals of adjacent nociceptors requires their common postsynaptic target, the A08n neurons. This phenotype is recapitulated by knockdown of the BMP ligand, Decapentaplegic (Dpp), in these neurons. In addition, removing the Type 2 BMP receptors or their effector (Mad transcription factor) in single nociceptors impairs the fine-scale topography, suggesting the contribution of BMP signaling originated from A08n. This signaling is likely mediated by phospho-Mad in the presynaptic terminals of nociceptors to ensure local interneuronal communication. Finally, reducing Dpp levels in A08n reduces the nociceptor-A08n synaptic contacts. Our data support that transsynaptic BMP signaling establishes the fine-scale topography by facilitating the formation of topographically correct synapses. Local BMP signaling for synapse formation may be a developmental strategy that independently regulates neighboring axon terminals for fine-scale topography.
Assuntos
Proteínas Morfogenéticas Ósseas , Proteínas de Drosophila , Células Receptoras Sensoriais , Transdução de Sinais , Animais , Proteínas de Drosophila/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Transdução de Sinais/fisiologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Drosophila , Larva , Nociceptores/metabolismo , Nociceptores/fisiologia , Animais Geneticamente Modificados , Sinapses/metabolismo , Sinapses/fisiologia , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/fisiologia , Proteínas de Ligação a DNA , Fatores de TranscriçãoRESUMO
The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (plus nerve growth factor), and pain-free conditions (Nav1.7-null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behavior. Terminal-enriched transcripts included those encoding synaptic proteins (e.g., synaptotagmin), non-coding RNAs, transcription factors (e.g., Znf431), proteins associated with transsynaptic trafficking (HoxC9), GABA-generating enzymes (Gad1 and Gad2), and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.
Assuntos
Dor , Células Receptoras Sensoriais , Animais , Células Receptoras Sensoriais/metabolismo , Camundongos , Masculino , Feminino , Dor/metabolismo , Biossíntese de Proteínas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Polirribossomos/metabolismo , Camundongos Endogâmicos C57BL , Gânglios Espinais/metabolismoRESUMO
Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd-/-) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Capsaicina , Receptores de Antígenos de Linfócitos T gama-delta , Rosácea , Células Receptoras Sensoriais , Animais , Rosácea/imunologia , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Receptoras Sensoriais/metabolismo , Capsaicina/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Pele/patologia , Pele/imunologia , Pele/metabolismo , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Dermatite/imunologia , Dermatite/metabolismo , Dermatite/patologia , Modelos Animais de Doenças , Masculino , Nociceptores/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Humanos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismoRESUMO
Electrical excitability-the ability to fire and propagate action potentials-is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage-gated sodium channels, and to fire action potential trains. Inactivating this signaling pathway in Schwann cells impairs somatosensory neuron maturation, causing multimodal sensory defects that persist into adulthood. Collectively, our studies uncover a neurodevelopmental role for prostaglandin E2 distinct from its established role in inflammation, revealing a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.
Assuntos
Potenciais de Ação , Dinoprostona , Células de Schwann , Células Receptoras Sensoriais , Animais , Células de Schwann/metabolismo , Dinoprostona/metabolismo , Camundongos , Células Receptoras Sensoriais/metabolismo , Transdução de SinaisRESUMO
Neuropathic pain is characterised by periodic or continuous hyperalgesia, numbness, or allodynia, and results from insults to the somatosensory nervous system. Peripheral nerve injury induces transcriptional reprogramming in peripheral sensory neurons, contributing to increased spinal nociceptive input and the development of neuropathic pain. Effective treatment for neuropathic pain remains an unmet medical need as current therapeutics offer limited effectiveness and have undesirable effects. Understanding transcriptional changes in peripheral nerve injury-induced neuropathy might offer a path for novel analgesics. Our literature search identified 65 papers exploring transcriptomic changes post-peripheral nerve injury, many of which were conducted in animal models. We scrutinize their transcriptional changes data and conduct gene ontology enrichment analysis to reveal their common functional profile. Focusing on genes involved in 'sensory perception of pain' (GO:0019233), we identified transcriptional changes for different ion channels, receptors, and neurotransmitters, shedding light on its role in nociception. Examining peripheral sensory neurons subtype-specific transcriptional reprograming and regeneration-associated genes, we delved into downstream regulation of hypersensitivity. Identifying the temporal program of transcription regulatory mechanisms might help develop better therapeutics to target them effectively and selectively, thus preventing the development of neuropathic pain without affecting other physiological functions.
Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Animais , Humanos , Neuralgia/genética , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Células Receptoras Sensoriais/metabolismo , TranscriptomaRESUMO
Interactions between the nervous system and the immune system play crucial roles in initiating and directing the type 2 immune response. Sensory neurons can initiate innate and adaptive type 2 immunity through their ability to detect allergens and promote dendritic cell and mast cell responses. Neurons also indirectly promote type 2 inflammation through suppression of type 1 immune responses. Type 2 cytokines promote neuronal function by directly activating or sensitizing neurons. This positive neuroimmune feedback loop may not only enhance allergic inflammation but also promote the system-wide responses of aversion, anaphylaxis, and allergen polysensitization that are characteristic of allergic immunity.
Assuntos
Alérgenos , Hipersensibilidade , Neuroimunomodulação , Humanos , Alérgenos/imunologia , Animais , Hipersensibilidade/imunologia , Citocinas/metabolismo , Citocinas/imunologia , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/metabolismo , Mastócitos/imunologiaRESUMO
Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.