Sensory Neuron Expressed TRPC3 Mediates Acute and Chronic Itch

2021 ◽  
Author(s):  
Yan Liu ◽  
Yutong Liu ◽  
Claire Narang ◽  
Nathachit Limjunyawong ◽  
Hanna Jamaldeen ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Small Diameter ◽  
Contact Hypersensitivity ◽  
Peripheral Sensitization ◽  
Primary Sensory Neurons ◽  
Proinflammatory Mediators ◽  
Chronic Itch

Abstract Background: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represent a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. However, the role of TRPC3 in acute and chronic itch is still not well defined. Methods: RNAscope in situ hybridization and immunohistochemical staining were performed on mouse trigeminal ganglion (TG) neurons. Fura-2 calcium imaging was used to characterize the function of TRPC3 in dissociated TG neurons. In native mice, the TRPC3 agonist and pruritogens were subcutaneously injected to the cheek and nape of the neck of mice, respectively. Site directed scratching and/or wiping behaviors were video recorded. Contact hypersensitivity (CHS) model was induced in mouse ears by topical application of SADBE or DNCB. Spontaneous scratching behaviors were recorded by video monitoring. Global and conditional Trpc3 knockout mice were employed to determine the contribution of TRPC3 to acute and chronic itch. The mRNA expression levels of Trpc3 and proinflammatory cytokines were assayed by quantitative real-time PCR. H&E. staining was used for the evaluation of the thickness of mouse ears. Flow cytometry was performed to assess immune cell infiltration in mouse ear tissues. Results: Among mouse TG neurons, RNAscope assay revealed that Trpc3 mRNA was predominantly expressed in nonpeptidergic small diameter neurons. Moreover, Trpc3 mRNA signal was present in the majority of itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch- and pain-like behaviors in naïve mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of CHS, Trpc3 mRNA expression level and function were upregulated in the TG following CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. Conclusions: These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch via a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

scholarly journals Molecular signature of pruriceptive MrgprA3+ neurons

2019 ◽  
Author(s):  
Yanyan Xing ◽  
Junyu Chen ◽  
Henry Hilley ◽  
Haley Steele ◽  
Jingjing Yang ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Neuronal Populations ◽  
Pathological Conditions ◽  
Chronic Itch ◽  
Itch Sensation ◽  
Profile Changes ◽  
Allergic Contact

ABSTRACTItch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

Peripheral, but not central, axotomy induces neuropilin-1 mRNA expression in adult large diameter primary sensory neurons

2000 ◽  
Vol 423 (3) ◽  
pp. 492-499 ◽  
Author(s):  
Isabella Gavazzi ◽  
Jonathan Stonehouse ◽  
Axel Sandvig ◽  
Julie N. Reza ◽  
Linda S. Appiah-Kubi ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Sensory Neurons ◽  
Large Diameter ◽  
Primary Sensory Neurons ◽  
Neuropilin 1

scholarly journals Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice

Pain ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 1613-1621 ◽  
Author(s):  
Zhe Li ◽  
Shao-Qiu He ◽  
Qian Xu ◽  
Fei Yang ◽  
Vinod Tiwari ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Sensory Neurons ◽  
Small Diameter ◽  
Primary Sensory Neurons

scholarly journals RAGE signaling sustains inflammation and promotes tumor development

2008 ◽  
Vol 205 (2) ◽  
pp. 275-285 ◽  
Author(s):  
Christoffer Gebhardt ◽  
Astrid Riehl ◽  
Moritz Durchdewald ◽  
Julia Németh ◽  
Gerhard Fürstenberger ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Tumor Development ◽  
Tumor Promotion ◽  
Tissue Reaction ◽  
Epidermal Hyperplasia ◽  
Proinflammatory Mediators ◽  
Glycation End Products ◽  
Direct Genetic Evidence

A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer.

scholarly journals The Calcium Channel α2δ1 Subunit: Interactional Targets in Primary Sensory Neurons and Role in Neuropathic Pain

2021 ◽  
Vol 15 ◽  
Author(s):  
Wenqiang Cui ◽  
Hongyun Wu ◽  
Xiaowen Yu ◽  
Ting Song ◽  
Xiangqing Xu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Calcium Channel ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Peripheral Sensitization ◽  
Primary Sensory Neurons ◽  
Transient Receptor ◽  
Underlying Mechanisms

Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N-methyl-D-aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

scholarly journals MTUS1 is Correlated with Immune Infiltration and Acts as a Promising Diagnostic and Prognostic Biomarker for Colorectal Cancer.

2021 ◽  
Author(s):  
cheng linyao ◽  
Hai-Ming Ru ◽  
Hua-Ge Zhong ◽  
Mao-sen Huang ◽  
Si-Si Mo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mrna Expression ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Human Life ◽  
Diagnostic Value ◽  
Clinicopathological Characteristics ◽  
The Cancer Genome Atlas ◽  
Multiple Cancer ◽  
Poor Overall Survival

Abstract Background：Colorectal cancer morbidity and mortality remain high, posing a serious threat to human life and health. Early diagnosis and prognostic evaluation are two major challenges addressed in clinical practice. MTUS1, is considered a tumor suppressor, plays important roles in inhibiting cell proliferation, migration and tumor growth. MTUS1 expression is decreased in a wide variety of human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain still ambiguous.Methods: In this study, the data from The Cancer Genome Atlas (TCGA) database was analyzed using R statistical software (version 3.6.3.) to elucidate the diagnostic and prognostic value of MTUS1. In addition, we detected MTUS1 expression in colorectal tumor tissue and adjacent normal tissue using the GEO, TIMER and ONCOMINE and investigated the relationship between MTUS1 expression and clinicopathological characteristics. The correlation between MTUS1 expression and immune infiltrating level was identified via TIMER and GEPIA database. Furthermore, we constructed and analyzed PPI network and co-expression modules of MTUS1 to explore molecular functions and mechanisms. Results: The CRC tissues exhibited higher MTUS1 mRNA expression levels than the normal tissues. The logistic regression analysis suggested that MTUS1 mRNA expression was associated with N stage, TNM stage, and neoplasm type. Patients with CRC exhibiting low MTUS1 mRNA expression were correlated with poor overall survival (OS). The multivariate analysis revealed that down-regulate expression of MTUS1 was an independent prognostic factor and was correlated with poor OS in patients with CRC. MTUS1 expression had a good diagnostic value based on ROC analysis. A group of potential MTSU1 interacting proteins and co-expressed genes was identified. GO and KEGG analyses showed that MTUS1 was involved in multiple cancer-related signaling pathways. Most importantly, MTUS1 expression was significantly related to the degree of multiple immune-cell infiltration. Moreover, MTUS1 expression strongly correlated with a variety of immune marker sets.Conclusions: Our results suggested that MTUS1 may serves a promising biomarker for predicting diagnosis and prognosis of CRC patients and is expected to become a new molecular target for tumor immunotherapy.

scholarly journals Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

2021 ◽  
Vol 11 ◽  
Author(s):  
Éva Borbély ◽  
Ágnes Hunyady ◽  
Krisztina Pohóczky ◽  
Maja Payrits ◽  
Bálint Botz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Immune Cell ◽  
Active Immunization ◽  
Fluorescent Imaging ◽  
Laser Speckle ◽  
Myeloperoxidase Activity ◽  
Primary Sensory Neurons ◽  
Protein Extravasation ◽  
Deficient Mice

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

scholarly journals Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
N. Muñoz-Durango ◽  
A. Vecchiola ◽  
L. M. Gonzalez-Gomez ◽  
F. Simon ◽  
C. A. Riedel ◽  
...  
Keyword(s):  
Immune System ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Scientific Work ◽  
Proinflammatory Mediators ◽  
Electrolyte Homeostasis

The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models.

scholarly journals Glutaminase Immunoreactivity and Enzyme Activity Is Increased in the Rat Dorsal Root Ganglion Following Peripheral Inflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Kenneth E. Miller ◽  
John C. Balbás ◽  
Richard L. Benton ◽  
Travis S. Lam ◽  
Kristin M. Edwards ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Dorsal Root Ganglion ◽  
Western Blot ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Peripheral Sensitization ◽  
Primary Sensory Neurons ◽  
Drg Neurons ◽  
Glutamate Production ◽  
Afferent Terminals

Following inflammation, primary sensory neurons in the dorsal root ganglion (DRG) alter the production of several proteins. Most DRG neurons are glutamatergic, using glutaminase as the enzyme for glutamate production, but little is known about glutaminase following inflammation. In the present study, adjuvant-induced arthritis (AIA) was produced in rats with complete Freund's adjuvant into the hindpaw. At 7 days of AIA, DRG were examined with glutaminase immunohistochemistry, Western blot immunoreactivity, and enzyme activity. Image analysis revealed that glutaminase was elevated most in small-sized neurons (21%) (P < 0.05). Western blot analysis revealed a 19% increase (P < 0.05) in total glutaminase and 21% in mitochondrial glutaminase (P < 0.05). Glutaminase enzyme activity was elevated 29% (P < 0.001) from 2.20 to 2.83 moles/kg/hr. Elevated glutaminase in primary sensory neurons could lead to increased glutamate production in spinal primary afferent terminals contributing to central sensitization or in the peripheral process contributing to peripheral sensitization.

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