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Dry skin induced chronic pruritus is an increasingly common and debilitating problem, especially in the elderly. Although keratinocytes play important roles in innate and adaptive immunity and keratinocyte proliferation is a key feature of dry skin induced chronic pruritus, the exact contribution of keratinocytes to the pathogenesis of dry skin induced chronic pruritus is poorly understood. In this study, we generated the acetone-ether-water induced dry skin model in mice and found that epidermal hyperplasia induced by this model is partly dependent on the β-catenin signaling pathway. XAV939, an antagonist of β-catenin signaling pathway, inhibited epidermal hyperplasia in dry skin model mice. Importantly, dry skin induced chronic pruritus also dramatically reduced in XAV939 treated mice. Moreover, acetone-ether-water treatment-induced epidermal hyperplasia and chronic itch were decreased in Trpv4 -/- mice. In vitro, XAV939 inhibited hypo-osmotic stress induced proliferation of HaCaT cells, and hypo-osmotic stress induced proliferation of in HaCaT cells and primary cultured keratinocytes were also significantly reduced by blocking TRPV4 function. Finally, thymic stromal lymphopoietin release was examined both in vivo and in vitro, which was significantly inhibited by XAV939 treatment and Trpv4 deficiency, and anti-TSLP antibody treatment significantly decreased AEW-induced scratching behavior. Overall, our study revealed a unique ability of TRPV4 expressing keratinocytes in the skin, which critically mediated dry skin induced epidermal hyperplasia and chronic pruritus, thus provided novel insights into the development of therapies for chronic pruritus in the elderly., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024. Published by Elsevier B.V.)

Background: Gaucher is an autosomal recessive inherited lysosomal storage disorder. The incidence of this disease is rare with a global estimate of around 1 in 57,000 to 1 in 75,000. Gaucher's disease is caused by a mutation in the glucocerebrosidase gene. Common symptoms of this disease include hepatosplenomegaly, moderate neurological symptoms, and late‑onset skeletal alterations. However, Gaucher can sometimes have rare presentations that lead to a delayed diagnosis in patients. This report discusses two adult cases of Gaucher's disease (type 1) with the same mutation but with unusual symptoms., Case Presentation: One patient was a 44-year-old man who had been experiencing chronic cough since he was 10 years old, and the other patient was a 27-year-old woman with itching, both atypical symptoms of Gaucher. Bronchodilators and prednisolone were administered for chronic cough and antihistamines and prednisolone were given for the itching, but little to no improvement was seen. Sonography tests revealed that both cases had splenomegaly, hepatomegaly, and liver malfunction, characteristic of Gaucher's disease. Bone marrow aspiration tests confirmed the presence of Gaucher's cells in their bones. The level of glucocerebrosidase enzyme in both cases was less than 1.5 nmol/mL/hour. Whole exon sequencing confirmed a mutation on exon 8 of the GBA1 gene in a homozygous form in both cases, resulting in a transversion mutation (C > G) at position c.798, leading to the substitution of phenylalanine 266 with leucine. Both patients were of Bakhtiyari ethnicity and had parents who were in a consanguineous marriage. After receiving Cerezyme treatment, both cases experienced a disappearance of their cough and itching symptoms., Conclusion: This report highlights the importance of recognizing the unusual presentation of Gaucher's disease especially in regions with high rates of consanguineous marriage and thalassemia. This knowledge can aid physicians in making accurate diagnoses and providing appropriate treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Consent was gained by all applicants in this study. Consent for publication: Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: None declared., (© 2024. The Author(s).)

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease resulting from inadequate type VII collagen (C7). Although recurrent skin blisters and wounds are the most apparent disease features, the impact of C7 loss is not confined to the skin and mucous membranes. RDEB is a systemic disease marred by chronic inflammation, fibrotic changes, pain, itch, and anemia, significantly impacting QOL and survival. In this narrative review, we summarize these systemic features of RDEB and promising research avenues to address them., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4 , IL-13 , and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.

Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue-specific transgenic mice, various itch models, behavior scoring, RNA sequencing, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice but upregulated skin protease-activated receptor 2 (PAR2) transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing PAR2 transcription and activity. Coinjection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. In addition, IL-27 boosted BST2 transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuron-specific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL-27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5 -/- mice (peripheral) but increased in LPAR2 -/- and Prg1 -/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2 -/- ) or Prg2 (PRG2 -/- ). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5 -/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.

Purpose: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood., Experimental Design: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays., Results: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo., Conclusions: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions., (©2024 The Authors; Published by the American Association for Cancer Research.)

Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca 2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Pathogenic variants in filaggrin (FLG) are associated with an increased risk of atopic dermatitis (AD)., Objective: We evaluated the influence of FLG variants on the effectiveness of dupilumab treatment in AD., Methods: This prospective observational study included adult AD patients treated with dupilumab from the BioDay registry. FLG was analyzed with single-molecule molecular inversion probe-targeted sequencing. Novel mutations were confirmed by Sanger sequencing. Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), numeric rating scale (NRS) pruritus, Dermatology Quality of Life Index (DLQI), and Patient-Oriented Eczema Measure (POEM) were assessed at baseline and at weeks 16 and 52. The study was registered at ClinicalTrials.gov as NCT03549416., Results: Genetic analysis of the 285 included patients showed biallelic pathogenic variants (FLG -/- ) in 41 (14%), monoallelic pathogenic variants (FLG -/+ ) in 64 (23%), and wild-type alleles (FLG +/+ ) in 180 patients (63%). Three novel pathogenic variants were found. We observed no clinically relevant differences in EASI, IGA, NRS pruritus, DLQI, or total POEM scores for patients with and without pathogenic FLG variants at all time points. The FLG -/- group showed significantly higher POEM flaking and dryness scores at week 16 (P < .001 and P = .002, respectively) and week 52 (P < .001 and P = .016, respectively) compared to FLG +/+ as well as significant differences compared to FLG -/+ , while differences in delta scores were nonsignificant., Conclusion: The effectiveness of dupilumab treatment in AD patients was not influenced by pathogenic FLG variants. However, patients with biallelic pathogenic FLG variants tended to have drier skin before and during dupilumab treatment compared to patients with monoallelic pathogenic variants or wild-type alleles., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pruritus, also known as itching, is a complex sensation that involves the activation of specific physiological and cellular receptors. The skin is innervated with sensory nerves as well as some receptors for various sensations, and its immune system has prominent neurological connections. Sensory neurons have a considerable impact on the sensation of itching. However, immune cells also play a role in this process, as they release pruritogens. Disruption of the dermal barrier activates an immune response, initiating a series of chemical, physical, and cellular reactions. These reactions involve various cell types, including keratinocytes, as well as immune cells involved in innate and adaptive immunity. Collective activation of these immune responses confers protection against potential pathogens. Thus, understanding the molecular and cellular mechanisms that contribute to pruritus in host skin is crucial for the advancement of effective treatment approaches. This review provides a comprehensive analysis of the present knowledge concerning the molecular and cellular mechanisms underlying itching signaling in the skin. Additionally, this review explored the integration of these mechanisms with the broader context of itch mediators and the expression of their receptors in the skin., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Itch is a unique sensory experience that is responded to by scratching. How pruritogens, which are mechanical and chemical stimuli with the potential to cause itch, engage specific pathways in the peripheral and central nervous system has been a topic of intense investigation over the last few years. Studies employing recently developed molecular, physiological, and behavioral techniques have delineated the dedicated mechanisms that transmit itch information to the brain. This review outlines the genetically defined and evolutionary conserved circuits for itch ranging from the skin-innervating peripheral neurons to the cortical neurons that drive scratching. Moreover, scratch suppression of itch is attributed to the concurrent activation of pain and itch pathways. Hence, we discuss the similarities between circuits driving pain and itch.

IL-31 receptor blockade suppresses pruritus of atopic dermatitis. However, cell-type-specific contributions of IL-31 receptor to itch, its expression mechanism, and the downstream signaling pathway to induce itch remain unknown. Here, using conditional knockout mice, we demonstrate that IL-31-induced itch requires sensory neuronal IL-31 receptor and STAT3. We find that IL-31 receptor expression is dependent on STAT3 in sensory neurons. In addition, pharmacological experiments suggest that STAT3 activation is important for the itch-inducing signaling downstream of the IL-31 receptor. A cutaneous IL-31 injection induces the nuclear accumulation of activated STAT3 first in sensory neurons that abundantly express IL-31 receptor and then in other itch-transmitting neurons. IL-31 enhances itch induced by various pruritogens including even chloroquine. Finally, pruritus associated with dermatitis is partially dependent on sensory neuronal IL-31 receptor and strongly on sensory neuronal STAT3. Thus, sensory neuronal STAT3 is essential for IL-31-induced itch and further contributes to IL-31-independent inflammatory itch., Competing Interests: Declaration of interests All authors declare that they have no relevant conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Animal models of skin disease are used to evaluate therapeutics to alleviate disease. One common clinical dermatological complaint is pruritus (itch), but there is a lack of standardization in the characterization of pre-clinical models and scratching behavior, a key itch endpoint, is often neglected. One such model is the widely used imiquimod (IMQ) mouse model of psoriasis. However, it lacks characterized behavioral attributes like scratching, nor has widely expanded to other species like rats. Given these important attributes, this study was designed to broaden the characterization beyond the expected IMQ-induced psoriasis-like skin inflammatory skin changes and to validate the role of a potential therapeutic agent for pruritus in our genetic rat model. The study included female Wistar rats and genetically modified knockin (humanized proteinase-activated receptor 2 (F2RL1) female rats, with the widely used C57BL/6 J mice as a methodology control for typical IMQ dosing., Results: We demonstrate that the IMQ model can be reproduced in rats, including their genetically modified derivatives, and how scratching can be used as a key behavioral endpoint. We systemically delivered an anti-PAR2 antibody (P24E1102) which reversed scratching bouts-validating this behavioral methodology and have shown its feasibility and value in identifying effective antipruritic drugs., (© 2023. The Author(s).)

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergic A11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1 + ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1 + neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1 + neurons form synapses with GRP receptor-expressing (GRPR + ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1 + neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1 + neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch., (© 2023 The Authors.)

Background: Spinal astrocytes contribute to chronic itch via sensitization of itch-specific neurons expressing gastrin-releasing peptide receptor (GRPR). However, whether microglia-neuron interactions contribute to itch remains unclear. In this study, we aimed to explore how microglia interact with GRPR + neurons and promote chronic itch., Methods: RNA sequencing, quantitative real-time PCR, western blot, immunohistochemistry, RNAscope ISH, pharmacologic and genetic approaches were performed to examine the roles of spinal NLRP3 (The NOD-like receptor family, pyrin-containing domain 3) inflammasome activation and IL-1β-IL1R1 signaling in chronic itch. Grpr-eGFP and Grpr KO mice were used to investigate microglia-GRPR + neuron interactions., Results: We observed NLRP3 inflammasome activation and IL-1β production in spinal microglia under chronic itch conditions. Blockade of microglial activation and the NLRP3/caspase-1/IL-1β axis attenuated chronic itch and neuronal activation. Type 1 IL-1 receptor (IL-1R1) was expressed in GRPR + neurons, which are essential for the development of chronic itch. Our studies also find that IL-1β + microglia are localized in close proximity to GRPR + neurons. Consistently, intrathecal injection of IL1R1 antagonist or exogenous IL-1β indicate that the IL-1β-IL-1R1 signaling pathway enhanced the activation of GRPR + neurons. Furthermore, our results demonstrate that the microglial NLRP3/caspase-1/IL-1β axis contributes to several different chronic itches triggered by small molecules and protein allergens from the environment and drugs., Conclusion: Our findings reveal a previously unknown mechanism in which microglia enhances the activation of GRPR + neurons through the NLRP3/caspase-1/IL-1β/IL1R1 axis. These results will provide new insights into the pathophysiology of pruritus and novel therapeutic strategies for patients with chronic itch., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Bile salt export pump (ABCB11) deficiency [Progressive familial intrahepatic cholestasis (PFIC2)] is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. Surgical biliary diversion or pharmacological [ileal bile acid transporter inhibitor (IBATi)] approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome., Methods: This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed., Results: Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis., Conclusion: Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Somatosensory neurons are highly heterogeneous with distinct types of neural cells responding to specific stimuli. However, the distribution and roles of cell-type-specific long intergenic noncoding RNAs (lincRNAs) in somatosensory neurons remain largely unexplored. Here, by utilizing droplet-based single-cell RNA-seq (scRNA-seq) and full-length Smart-seq2, we show that lincRNAs, but not coding mRNAs, are enriched in specific types of mouse somatosensory neurons. Profiling of lincRNAs from single neurons located in dorsal root ganglia (DRG) identifies 200 lincRNAs localized in specific types or subtypes of somatosensory neurons. Among them, the conserved cell-type-specific lincRNA CLAP associates with pruritus and is abundantly expressed in somatostatin (SST)-positive neurons. CLAP knockdown reduces histamine-induced Ca 2+ influx in cultured SST-positive neurons and in vivo reduces histamine-induced scratching in mice. In vivo knockdown of CLAP also decreases the expression of neuron-type-specific and itch-related genes in somatosensory neurons, and this partially depends on the RNA binding protein MSI2. Our data reveal a cell-type-specific landscape of lincRNAs and a function for CLAP in somatosensory neurons in sensory transmission., (© 2022 The Authors.)

Scratching and scratch-induced injuries, including neuroanatomical alterations, are key characteristics of chronic pruritus entities of different origins. The aim of this study was to link gene expression (array hybridization, qPCR) with DNA methylation (array hybridization) and neuroanatomy (PGP9.5 staining) in chronic nodular prurigo (CNPG), atopic dermatitis (AD), brachioradial pruritus (BRP), and matched healthy controls. Specific signatures of gene expression and DNA methylation clearly discriminated pruritic lesional skin from nonpruritic skin in CNPG and from healthy skin of volunteers, respectively. Although intraepidermal nerve fiber density was indiscriminately reduced, the level of epidermal branching, assessed by a semiquantitative pattern analysis, differentiated the entities (CNPG > BRP > AD). Correspondingly, repellent SEMA3A showed the highest expression in AD, whereas axonal growth-promoting nerve GF was most prominent in CNPG and BRP. Overexpression of genes for nerve fiber regeneration (NELL2/NFKB/ARTN) was found in AD and CNPG but not in BRP. Our findings suggest that differential branching patterns rather than mere innervation density separate chronic itch conditions and reflect disease-specific local expression profiles. In pruritic dermatoses (AD and CNPG), nerve injury and subsequent sprouting may primarily result from chronic scratching, whereas genuine neuropathy is expected to underlie BRP., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is a common skin disease caused by genetic and environmental factors. However, the mechanisms underlying AD development remain unclear. In this study, we examined the genetic factors contributing to the onset of itch-associated scratching in different strains of mice. Interleukin-31 (IL-31) induces severe scratching and dermatitis in mice. However, the site of action of IL-31 remains unclear. Cutaneous IL-31 and IL-31 receptor A (IL-31RA) mRNAs in the dorsal root ganglion (DRG) are expressed exclusively in the AD model, i.e., NC/Nga mice. Here we evaluated the effects of repeated administration of IL-31 on the scratching behavior in NC/Nga, BALB/c, and C57BL/6 mice. The results showed that repeated administration of IL-31 significantly increased itch-associated scratching (LLS) behavior in the three strains of mice. One hour after an intravenous IL-31 injection, BALB/c mice showed alloknesis-like behavior. Mite infestation and IL-31 administration triggered itchy skin, increased LLS counts and DRG neuronal IL-31RA expression, and eventually caused dermatitis. The dermatitis severity and LLS counts induced by mite infestation and IL-31 administration were in the order NC/Nga > BALB/c > C57BL/6. In conclusion, neuronal IL-31RA expression in the DRG was the most important genetic factor affecting the severity of LLS and dermatitis in mice.

Prurigo nodularis (PN), characterized by inevitable chronicity and severe pruritus, is most frequently associated with atopy compared with other origins. However, the skin transcriptomic profiling of PN arising from atopic dermatitis (AD), so-called atopic PN (APN), remains unclear. We sought to explore the cutaneous transcriptome of APN with severe pruritus and compare it with classic AD. RNA sequencing was performed on the lesional skin from 13 APN to 11 AD patients with severe pruritus (itch numerical rating scale score ≥ 7) and normal skin from 11 healthy subjects. Quantitative real-time polymerase chain reaction and immunochemistry were used for validation. We detected 1085 and 1984 differentially expressed genes (DEGs) in lesional APN skin and lesional AD skin versus normal skin, respectively. In total, 142 itch/inflammation-related DEGs were identified. Itch/inflammation-related DEGs, such as IL-6, IL-10, IL-13, oncostatin M, and IL-4 receptor, had elevated gene transcript levels in both diseases. The itch/inflammation-related DEGs that increased only in APN were mainly neuroactive molecules, while many inflammatory mediators such as T helper 22-related genes were found to be increased only in AD. Both disorders showed mixed Th1/Th2/Th17 polarisation and impaired skin barrier. In contrast to AD, M1/M2 macrophage activation, tumor necrosis factor production, fibrosis, revascularization and neural dysregulation are unique features of APN. The study findings broaden our understanding of the pathogenesis underlying APN, which provides insights into novel pathogenesis with potential therapeutic implications., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents 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. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive 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 contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after 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. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders., (Copyright © 2022 International Association for the Study of Pain.)

Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch through transient receptor potential channels signaling are poorly understood. In this study, we show that genetic deletion or pharmacological antagonism of TRPV4 attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several microRNAs, including the miR-203b-3p, which induced a calcium ion response in rodent dorsal root ganglion neurons and scratching behavior in mice through 5-HTR2B activation and the protein kinase C‒dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular microRNA that can behave as an itch promoter through 5-HTR2B and TRPV4., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The dry skin tortures numerous patients with severe itch. The transient receptor potential cation channel V member 1 (TRPV1) and A member 1 (TRPA1) are two essential receptors for peripheral neural coding of itch sensory, mediating histaminergic and nonhistaminergic itch separately. In the dorsal root ganglion, transmembrane protein 100 (TMEM100) is structurally related to both TRPV1 and TRPA1 receptors, but the exact role of TMEM100 in itch sensory coding is still unknown. Here, in this study, we find that TMEM100 + DRG neurons account for the majority of activated neurons in an acetone-ether-water (AEW)-induced dry skin itch model, and some TMEM100 + DRG neurons are colocalized with both TRPA1 and the chloroquine-related Mrgpr itch receptor family. Both the expression and function of TRPA1 channels, but not TRPV1 channels, are upregulated in the AEW model, and specific DRG Tmem100 gene knockdown alleviates AEW-induced itch and rescues the expression and functional changes of TRPA1. Our results strongly suggest that TMEM100 protein in DRG is the main facilitating factor for dry-skin-related chronic itch, and specific suppression of TMEM100 in DRG could be a novel effective treatment strategy for patients who suffer from dry skin-induced itch.

Ethnopharmacological Relevance: In treating atopic dermatitis, multi-mode management is adopted, including trying to avoid the allergens, controlling and preventing secondary infections, and using drugs to control itching. At present, most of the commonly used anti-pruritic drugs in the clinic are single-target and lead to serious side effects. Many studies have shown that a variety of traditional Chinese medicines have significant anti-inflammatory and anti-pruritic effects, and have the characteristics of multiple components, multiple targets, and multiple effects., Aim of the Study: The study aimed to explore the anti-inflammatory and anti-pruritic effects of the Chi-Huang Solution in a murine model of Allergic contact dermatitis (ACD). This study considers the effectiveness of the Chi-Huang Solution for external use on skin to provide an experimental basis for the clinical development and application of Chinese medicine and related preparations for Canine atopic dermatitis (CAD)., Materials and Methods: Forty-two male SPF C57BL/6 mice were randomly divided into control group (n = 6), ACD model group (n = 6), HAC control group (n = 6), and 4 Chi-Huang Solution groups (n = 6 in each group). With SADBE induce the murine model of ACD chronic pruritus, and initially evaluate whether the model is successful by counting scratching behavior, measuring the skin fold thickness and skin lesion score within 1 h. After treating the ACD model mice with deionized water, HAC, 1CH, 2CH, 3CH, and 4CH for 7 days, behavioral changes were used to evaluate the anti-pruritic effect. The skin fold thickness, skin lesion score, and spleen index were used to evaluate the anti-inflammatory effect of the Chi-Huang Solution. H.E. staining was used for the epidermal thickness measurement and pathological evaluation. RT-qPCR was used to analyze the mRNA expression of related inflammatory factors such as IL-1β, TNF-α, IL-33, IL-4, IL-17A, CXCL10, and its receptor CXCR3 in the skin of the lesion site, as well as to detect the mRNA expression of pruritus-related genes such as TRPV1, TRPA1, and GRP in DRG., Results: After the treatment of low-dose (0.1 g/mL) and medium-dose (0.2 g/mL) Chi-Huang Solution, the scratching times both decreased significantly (P < 0.05), meanwhile the medium-dose Chi-Huang Solution had an obvious effect on reducing scratches/scab score (P < 0.05). Moreover, no matter what dose it takes, all Chi-Huang Solution can alleviate the epidermal thickening (P < 0.05) and the infiltration of mast cells in the ACD murine model of ACD. It is worth mentioning that the count of mast cells in the dermis was significantly down-regulated after the treatment of medium-dose Chi-Huang Solution (P < 0.005). Furthermore, Chi-Huang Solution can significantly down-regulate the mRNA expression of related inflammatory factors in the skin, and reduce the mRNA expression of pruritus-related genes, such as TRPA1, TRPV1, and GRP in the spinal cord., Conclusions: The results indicated that Chi-Huang Solution for external use exhibits significant anti-inflammatory and anti-pruritic effects on SADBE-induced ACD chronic pruritus murine models. Chi-Huang Solution might emerge as an effective drug for the treatment of CAD and high-dose Chi-Huang Solution (0.4 g/ml) has better comprehensive effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Heterozygous defects in genes implicated in Progressive Familial Intrahepatic Cholestasis have been described in milder forms of cholestatic diseases. Our aim is to describe clinical, laboratory and imaging characteristics as well as treatment and outcome of a cohort of pediatric patients with heterozygous mutations in ATP8B1, ABCB11 or ABCB4., Patients and Methods: We present a retrospective descriptive study including pediatric patients with at least one heterozygosis defect in ATP8B1, ABCB11 or ABCB4 diagnosed after a cholestatic episode. Clinical, diagnostic and outcome data were collected including gene analysis (panel of PFIC NextGeneDx®)., Results: 7 patients showed a heterozygous mutation: 3 patients in ABCB4, 1 in ABCB11, 2 in ABCB4 and ABCB11 and 1 in ATP8B1. The median onset age was 5.5 years with a median time of follow-up of 6 years. The initial presentation was pruritus followed by asymptomatic hypertransaminasemia and persistent cholestasis. Two patients had family history of gallbladder stones and mild hepatitis. All showed elevated transaminases and bile acids, high gamma glutamyl-transferase (GGT) in 3 and conjugated bilirubin in 2 patients. Liver biopsy showed inflammatory infiltrate or mild fibrosis with normal immunohistochemistry. All patients were treated with ursodeoxycholic acid, two patients requiring the addition of resincholestyramine. During follow-up, 3 patients suffered limited relapses of pruritus. No disease progression was observed., Conclusion: Heterozygous mutations in genes coding proteins of the hepatocellular transport system can cause cholestatic diseases with great phenotypic variability. The presence of repeated episodes of hypertransaminasemia or cholestasis after a trigger should force us to rule out the presence of these heterozygous mutations in genes involved in CIFP., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

Itch triggers scratching, a behavioural defence mechanism that aids in the removal of harmful irritants and parasites 1 . Chemical itch is triggered by many endogenous and exogenous cues, such as pro-inflammatory histamine, which is released during an allergic reaction 1 . Mechanical itch can be triggered by light sensations such as wool fibres or a crawling insect 2 . In contrast to chemical itch pathways, which have been extensively studied, the mechanisms that underlie the transduction of mechanical itch are largely unknown. Here we show that the mechanically activated ion channel PIEZO1 (ref. 3 ) is selectively expressed by itch-specific sensory neurons and is required for their mechanically activated currents. Loss of PIEZO1 function in peripheral neurons greatly reduces mechanically evoked scratching behaviours and both acute and chronic itch-evoked sensitization. Finally, mice expressing a gain-of-function Piezo1 allele 4 exhibit enhanced mechanical itch behaviours. Our studies reveal the polymodal nature of itch sensory neurons and identify a role for PIEZO1 in the sensation of itch., (© 2022. The Author(s).)

Chronic itch is a complex sensation of the skin frequently associated with skin diseases, such as atopic dermatitis (AD) and psoriasis. Although Serpin E1 is implicated in chronic itch, its receptor and signaling pathways involved in itch are not known. In this study, the clinical relevance of a putative Serpin E1 receptor PLAUR to chronic itch, and the neuro-cutaneous Serpin E1-PLAUR signaling are explored. We found that PLAUR is overexpressed in skin specimens of human lesional AD and lesional psoriasis, and sensory neurons innervating MC903-induced AD-like murine skin. Murine PLAUR + sensory neurons responded to Serpin E1, resulting in enrichment of numerous itch- and inflammation-related genes and their protein release. PLAUR resides in TLR2 + neurons and Serpin E1 stimulus led to transcriptional upregulation of TLR2 and its co-signaling proteins. Agonists of TLR2 propagated itch-related gene transcription including BNP, OSM, and PAR2. OSM induced acute itch in mice and promoted G-CSF and IL-8 release from human keratinocytes. Serpin E1 inhibitor reduced MC903-induced itch, epidermal hyperplasia, immunocyte infiltration, and resulted in lower transcription/expression levels of Serpin E1 and OSM. Taken together, the PLAUR-TLR2-OSM signaling promotes skin-nerve communication, cutaneous inflammation, and itch, all feeding into an aggravation of AD and exaggerated itch circuits., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

An excitatory neuron subset in the spinal dorsal horn (SDH) that expresses gastrin-releasing peptide receptors (GRPR) is critical for pruriceptive transmission. Here, we show that glutamatergic excitatory inputs onto GRPR + neurons are facilitated in mouse models of chronic itch. In these models, neuronal pentraxin 2 (NPTX2), an activity-dependent immediate early gene product, is upregulated in the dorsal root ganglion (DRG) neurons. Electron microscopy reveals that NPTX2 is present at presynaptic terminals connected onto postsynaptic GRPR + neurons. NPTX2-knockout prevents the facilitation of synaptic inputs to GRPR + neurons, and repetitive scratching behavior. DRG-specific NPTX2 expression rescues the impaired behavioral phenotype in NPTX2-knockout mice. Moreover, ectopic expression of a dominant-negative form of NPTX2 in DRG neurons reduces chronic itch-like behavior in mice. Our findings indicate that the upregulation of NPTX2 expression in DRG neurons contributes to the facilitation of glutamatergic inputs onto GRPR + neurons under chronic itch-like conditions, providing a potential therapeutic target., (© 2022. The Author(s).)

Introduction: Associations between genetic variation and clinical conditions suggest that single nucleotide polymorphisms (SNPs) might correlate with postburn outcomes. COMT modulates catecholamine metabolism, and polymorphisms within the rs4680 allele result in variable enzyme activity. Catechol-amines are known to modulate the inflammatory process and may affect scar formation. The aim of this study was to determine whether variants in the rs4680 SNP of the COMT gene are associated with post-burn pruritus and scarring., Methods: Adult burn patients, admitted between 2007 and 2017, with deep partial-thickness burns or delayed healing provided blood samples for genotyp-ing and self-reported itch scores within 1 year of injury. Scarring was measured using the Vancouver Scar Scale (VSS). Itch scores ≥ 4 and VSS scores >7 were considered severe. Genomic deoxyribonucleic acid was genotyped for the rs4680 SNP using realtime polymerase chain reaction (PCR)., Results: Median itch and VSS scores were highest for GG homozygotes and lowest for AA homozygotes. This difference was statistically significant for VSS score (P < 0.0001) and approached significance for itch (P = 0.052). After accounting for confounding variables, including race/ethnicity, age, sex, and burn size, the GG homozygotes demonstrated worse scarring (odds ratio 1.88, P = 0.005) compared to AG heterozygotes whereas the AA homozygotes trended towards a protective effect against scarring (odds ratio 0.71, P = 0.10). itch did not demonstrate a statistically significant difference between rs4680 genotype., Conclusions: Our analysis identifies a trend between COMT genotype with scarring, with rs4680 genetic variation constituting an independent risk factor for VSS score., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch-scratch cycle., Objective: We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab., Method: RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti-IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines., Results: Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including T H 2/IL-13 and T H 17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function., Conclusion: These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled., (© 2022. The Author(s).)

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1 . However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the G i -couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via G q -couped PLCβ-Ca 2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca 2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice., Competing Interests: QM, XL, XL, JL, AM, DB, BL, HJ, YS, QY, FG, LW, JP, JJ, KS, RK, JY, AT, ZC No competing interests declared, (© 2021, Meng et al.)

Although histamine is a well-known itch mediator, histamine H 1 -receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.

Allergic contact dermatitis (ACD) is a common inflammatory dermatosis characterized by persistent itch and pain after topical contact with reactive chemicals. Although it has been long recognized as a type-IV hypersensitivity, its complexity of pathophysiology mechanism makes it still a clinical aporia in treatment. In this study, we aimed to identify crucial proteins involved in the nociceptive sensation of ACD. Based on a chemical-induced ACD murine model, we collected trigeminal ganglions of ACD and control mice for quantitative tandem mass tag (TMT)-labeling proteomic analysis. Immunohistochemistry was further practiced to validate the bioinformatic analysis. A total of 7685 proteins were identified and analyzed. Sixty-four proteins were significantly upregulated, and 75 proteins were downregulated in ACD mice. GO analysis demonstrated that the changed proteins were significantly enriched in terms of immune and peptidase activity in ACD mice. Proteins involved in the complement and coagulation cascades were notably changed in the KEGG enrichment analysis. The upregulation of complement component 3 (C3) in trigeminal satellite cells of ACD mice was further confirmed by immunohistochemistry. ACD upregulated C3 in trigeminal satellite cells. The complement system in sensory ganglion might play an essential role in forming pruritic and nociceptive sensations in ACD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER + neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER + neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER + neurons abrogated itch responses, indicating that GPER + neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER -/- rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating µ opioid signaling. SIGNIFICANCE STATEMENT Therapeutic options for itch are limited because of an as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathologic conditions. GPER + neurons (largely GABAergic) in the RVM are antipruritic neurons under tonic opioidergic inhibition, activation of GPER promotes phosphorylation of MOR and disinhibition of the antipruritic GPER + neurons from inhibitory opioidergic inputs, and failure to mobilize GPER + neurons may result in the exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain, and opioid analgesia and the paradoxical effects of morphine on pain and itch., (Copyright © 2021 the authors.)

This case describes a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome with diffuse eczematous dermatitis and severe, intractable pruritus. Despite a bone marrow transplant and immunosuppressive therapy, his skin findings and pruritus persisted. Off-label dupilumab provided significant improvement and almost complete clearance of the dermatitis and pruritus. This is the first known report of dupilumab being used in a patient with IPEX syndrome., (© 2021 Wiley Periodicals LLC.)

Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca 2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca 2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.

A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of Cck + -, Nptx2 + -, Nmb + -, and Crh + -expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non-NK1R-expressing projection neurons., Competing Interests: The authors declare no competing interest.

Background & Aims: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus., Methods: Pruritogenicity of lysophosphatidylcholine (LPC), LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca 2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a., Results: LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1 + sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates., Conclusions: We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1 + pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization., Competing Interests: Author MS was employed by company Hamad Medical Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meng, Li, Fischer, Steinhoff, Chen and Wang.)

The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted syndrome in humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive therapeutics for skin inflammation., Competing Interests: QL, JW, XW, JH, CP, YG, CX, PW, PC, ZC, YY, DL, JY No competing interests declared, (© 2021, Liu et al.)

We describe an 11-year-old girl with PLACK Syndrome (peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads), who was found to have a novel homozygous variant in CAST, the pathogenicity of which was confirmed using blood-derived RNA. There is no established treatment for PLACK syndrome. However, we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids, which prompted us to consider a potential treatment strategy. Indeed, we initiated this patient on intravenous lipid infusion (Vitalipid®; an emulsion of fat-soluble vitamins and lipofundin-MCT/LCT 20%) and the response was dramatic. Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement. PLACK syndrome is a very rare genodermatosis and only six families have been described to date with pathogenic CAST variants. This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition. The remarkable response we report and the relative safety of the intervention should prompt healthcare providers who care for PLACK syndrome patients to explore this as a potential treatment strategy in future studies., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)