Protein kinases: drug targets for immunological disorders

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(12), P. 787 - 806

Published: May 15, 2023

Language: Английский

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Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 152(2), P. 420 - 435

Published: May 18, 2023

Language: Английский

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Molecular taxonomy of nociceptors and pruriceptors

Pain, Journal Year: 2023, Volume and Issue: 164(6), P. 1245 - 1257

Published: Jan. 25, 2023

1. Introduction The ability to feel the warmth of sun or coolness a breeze on summer's day; pleasant caress skin; explore texture, size, and shape an object; pain as mechanism protect us from what is dangerous around has fascinated mankind for centuries. Perhaps this fascination rooted in fact that somatic senses temperature, pain, touch, itch, proprioception endow with continuously stay contact world within us. Attempting explain how we react heat, 17th century philosopher René Descartes depicted thread connecting skin brain particles fire pulling thread.20 In 1880s, distinct sensory spots were recognized shown respond specific stimuli, such cold. This finding was taken evidence different sensations relying existence nerves tuned types stimuli.83,94 beginning 20th century, discovery nerve fiber conduction velocities, activation thresholds, refractory periods made it possible link unique qualities sensation, kinds touch. Unlike innocuous touch pressure, which are communicated through fibers responding only mechanical noxious stimuli found activate class polymodal nociceptive several unpleasant including high-threshold force intense heat.7,12 work led general idea capacity discriminate perceptual arises functions variety neurons involved sensation. because neuron transduce certain, but not all, warm cool temperatures, cold, light punctate painful sharp objects, hair pull, chemical irritants, inflammatory substances, various vibration.29,38 Apart providing awareness about our body its surroundings, somatosensory system also essential other perform effortlessly without much thought. For example, continuous flow information sensory–motor feedback loop involving dozen muscles necessary coordinate movements when taking sip glass water seemingly simple task walking. Somatosensory organized discreet pathways autonomic sympathetic parasympathetic motor driving reflexes physiological homeostasis, thermoregulation reflex control sweat glands selective vasoconstrictor systems muscle active standing up during hypothermia, respectively.16,49,74 Furthermore, involve discriminative perception coordination efferent emotional motivational components important behavior. social hugging caressing induce pleasantness facilitate bonding, affiliative behavior, well-being,82,88 while convey protective include affective-motivational dimension unpleasantness contributing long-term behavior avoiding harm.112,125 molecularly coding each quality somatosensation unlikely. Instead, summation activity inactivity likely contribute dimensions involved. Several recent studies support conjecture, eg. sensation simultaneous warmth-sensing inhibition cold-sensing nerves97; requirement affective coping elicited by same stimuli45; suppression cold (−10 10°C) Calca+ neurons18,81; modulation touch-evoked itch Merkel cells Slc17a8-lineage (low-threshold mechanoreceptor [LTMR]) neurons32,33,108; alleviation Npy2r+ neuron-dependent acute A-LTMR neurons.3 With thorough molecular categorization types, experiments can be designed even greater precision, opening possibilities gaining new, deeper insights into cellular basis nociception pruriception. 2. Categorizing Sensory have historically been classified based properties, morphology, target innervation, spinal termination, developmental hierarchy, functional neurochemical properties (reviewed Emery Ernfors, 202029). instrumental deciphering peripheral nervous organized. However, these strategies measured so quantitative features, response stimuli; velocity; size; handful marker genes, might sufficient reliable identification units. By contrast, single-cell RNA sequencing (scRNA-seq) measure thousands quantitative, allows unbiased classification cell types. Nevertheless, accuracy cell-type assignment affected data (library complexity, depth, technical errors, noise) proportion messenger (mRNA) molecules successfully converted sequencing. addition, contain quantities mRNAs resulting differences quality, affecting assignment. particularly relevant which, unlike most central system, highly variable size. Cell-type resolution used clustering. aim clustering scRNA-seq identify diverse represent all taxonomies hampered questions "what relation between features function?" type?"152 intimately associated surrounding sheath satellite glial often insufficiently removed sample preparation. Single-nucleus (snRNA-seq) mitigate this. Although cell's genomic accessed nucleus alone, there less starting material cytosol included leading lower median number genes detected per presence ambient confounding classification. Gene capture vital metric, although ease improved snRNA-seq increasing analyzed cells, biological function lost due detection smaller expressed cell. Because this, always favored generated will review focus results obtained method. published heterogeneity mouse dorsal root ganglion (DRG),14,60-62,114,137,151 trigeminal,65,91,145 jugular60 neurons, lack efforts integrate find recurrent populations across using computational strategies. purpose, intersample mapping propagate machine deep-learning neural correlates studies60,61,131,151 well study DRG Sharma et al.114 know sequenced studies, taxonomy heavily influenced revealed studies. 3. Strategy along axis General present trigeminal ganglia, superior inferior (jugular) ganglia glossopharyngeal vagal nerves, DRG, very small geniculate ganglion.19,133 some accessory may XIth cranial nerve. located face oral cavity (including dura mater teeth, respectively), lips mouth having greatest representation. Neurons jugular innervate parts head, ear, throat cutaneous deep rest body. detect relay conscious sensations, visceral largely regulating homeostasis related organ transmitting gustatory taste buds.60,79,136,140 These petrosal nodose dedicated ganglia. Comparing trigeminal, jugular, identified suggests neuronal conserved axis, represented completely neurons.60 colonic neurons43 suggesting innervation. yet compared sets strategies, thus, similarities remain explored. 4. Overview their putative Based presented here, 19 predicted. An overview expression transducers, percent contribution ganglion, key markers, outlined Figure figure shows hierarchical adult transcription factors growth factor receptors known drive diversification development. Interestingly, reflects ontogeny.Figure 1.: Molecular relationship data. Usoskin al. (2015), Zeisel (2018), (2020), nomenclature follows Ernfors (2020) indicated at end branch tree. first top box represents conflation hierarchically summarizing type (C, Aδ, Aβ), modalities evidenced experimentation predicted (M, mechanical; H, heat; HTMR, mechanoreceptor; LTMR, low-threshold mechanoreceptor). Boxes bottom: type, major transduction expressed, percentage representation among innervation targets, examples finally neurons. Question mark indicates prediction expression. Note reflect ontogeny tree receptors. neurogenic Neurogenin-2 (Ngn2) drives early neurogenesis generating Aδ nociceptor, Aβ proprioceptor diversify transcriptional activation, repression, signaling Trk Ret Neurogenin-1 responsible later born defined Runx1, Prdm12, TrkA mostly unmyelinated pruriceptive Nppb, natriuretic peptide precursor B; scRNA-seq, sequencing; Sst, somatostatin.Neurons atlas mechanoreceptors 1 Aδ-LTMR, rapidly adapting (RA) slowly (SA) proprioceptor, C-LTMR, showing overall consistency units explored human.2,38,154 focusing LTMRs, interesting note 2 seem separate LTMRs types: rate adaptation velocity. underlying could mutually exclusive entities defining LTMR A-LTMRs does termination morphology. RA-LTMR scRNA-sequencing,114,131,151 terminates longitudinal lanceolate endings follicles Meissner Pacinian corpuscles.38 SA-LTMR terminate either putatively circumferential follicles. Machine learning–based analyses al.,131 al.,151 al., 2021114,131,151 (from now refer "Usoskin," "Zeisel," "Sharma" brevity) independently nociceptor pruriceptor varying resolution. low-resolution view reveals divisions whereas high individual subtypes identified. At resolution, 14 nociceptors pruriceptors C-fiber Aδ-fiber properties. conflated 7 relationships. We believe functionally similar many transducers Trpm8, Trpv1, Trpm2, Trpm3, Piezo2, multitude consistent both high-resolution taxonomy. following nomenclature: TrpM8high, PEP1-3, NP1-3. full includes 3 "TrpM8" 4 mechano-heat (peptidergic "PEP1" neurons), Aδ-nociceptor (putative heat peptidergic "PEP2" (A-HTMR) "PEP3" Mrgprd+ withdrawal β-alanine (nociceptor "NP1" Mrgpra3 "NP2" somatostatin (Sst) B (Nppb) expressing allergic possibly "NP3" neurons) (Fig. 1). units, shown. PEP1 subtypes, demonstrated one Conversely, proprioceptive neurons,114,131,151 heterogeneity, corresponding Ia, Ib, II endings.95,144 Mrgprb4 described135 It embedded NP2 neurons72 fails scarcity. Better additional expected cells. 5. Cross-species nonhuman primate (NHP, rhesus macaque) scRNA-seq.61 Integration co-clustering learning comparisons high-quality NHP species, basal layout species.61 looking level observed, directly relate stimuli. Transcriptomic analysis human performed spatial transcriptomics128 snRNA-seq.90 There validated transcriptomics. Therefore, transcriptomics extensively analyzed.128 Nguyen al.90 15 clusters (predicted H1-H15) mouse–human counterparts variably co-clustering. mapped back any counterpart (H4 H12 clusters), others showed resemblance (H1, H2, H5 corresponded C-polymodal subtypes; H8 TrpM8high neurons; H9 PEP3; H10 NP1; H11 NP3; H13 Aδ-LTMRs; H14 Aβ-LTMRs; H15 proprioceptors; C-LTMRs found), markers inconsistencies observed comparison. give indication somatosensation; however, further needed understand exact makeup. NHP, current open shaping physiology. Below describe where laboratories strategies120,138,156 summarize those interested interactive reading, single web site option select nomenclatures ("Usoskin," "Sharma") querying gene (https://ernforsgroup.shinyapps.io/MouseDRGNeurons/) containing STRT2 SmartSeq2 macaque (https://ernforsgroup.shinyapps.io/macaquedrg/). Expression makes sense placed Thus, understanding goes wrong chronic pain. centered rather than disproportionate impact examining genetic ablation synthetic inactivation optogenetics chemogenetics mice. reviews topic.2,3,45,70,87,94,112Figure 2.: Schematic "Sharma," "Kupari Usoskin" nomenclatures. mechanoreceptor. NA, available.6. C-cold-sensing Mouse named "high" (PEP3, see below) another expresses level. small-sized critical importantly sensing They esophagus,56,150 representing 6% 8% neurons.21 Trpm8 Foxp2 lacks mechanosensitive channel Piezo2 heat-sensitive TRP channels (ie, Trpa1, Trpm3). neuron, subtypes. difference strategy types.61 myelination, C fiber.151 Whether distinguished remains Intriguingly, Trpm8+ Ca2+ imaging: temperatures (28-20°C), (<18°C), third hybrid response.148 Consistent unimodality knockout TRPM8 transducer mouse.4,17,22 Mice lacking display clearly reduced aversive toward indicating ion contributes to, for, ablating entire population leads complete loss sensitivity mice knocked out.57,87,101 highlight significant role sensing, simultaneously participate independent conclusion supported set experiments. Low-threshold cold-sensitive unimodal stimuli.76 Among Scn10a (Nav1.8). Consistently, deleting Nav1.8 no effect down 5°C extreme (below freezing) absent.73 Moreover, (CGRP) Scn10a+ unknown TRPM8-independent "silent" sensitized neuropathic allodynia.75 proposed alternative transducers11,76 helped identifying remaining Trpm8-null mice, furthermore, below freezing seems regardless tissue damage.118 Finally, take part cold-induced analgesia, suppress pain.103 7. C-mechano-pruriceptors NP1, NP2, NP3 classes mechanosensory reflexes, potentially nociception. express thermosensitive and, according recordings least sensitive, vivo humans negligible.13,37,45,55,66,101 NP1 closer other.61,151 chemosensitive Trpv1 Trpa1 NP-class signal histamine nonhistamine itch-inducing compounds sensors.53,143 Forced MrgprdCre lineage NP3) generate place naive animals.139 none NP bona fide nociceptors, ie, encode stimuli.139 Chemical mediated whose patterns NHP. Exogenous endogenous mediators released damaged infected tissues increase extravasation vessels attracting immune injured response.77 "inflammatory soup" rich purines, amines, cytokines, chemokines, lipid mediators, factors. histamine, serotonin, leukotrienes, prostaglandins, bradykinin, sensitize thereby mediate As below, differentially threshold itch. taxonomy, conducted nociceptors.52,110 8. C-mechanopruriceptor nonpeptidergic NP1-type diameter, Mrgprd superficial layer epidermis glabrous hairy mouse.156 25% 32% pruriception (von Frey). eg, Mrgprd, Mrgprx receptors, Lpar3, Mdfic2. defines define clusters.61 determined. recordings, activated mechanical, chemical, rodents26,66,71,105; evoked von Frey filaments, affect sensation.13,45 they dispensable pinching.44 activating (NP1-3),139 animal,6,139 do after spared injury inflammation (using Freund adjuvant).1,139 state, Still, integrated allodynia especially needs systematically evaluated. mouse, histamine,66 β-alanine, natural pruritogenic compound, binds activates MRGPRD receptor,117 then engages TRPA1 induces itch.141 lysophosphatidic acid receptor Lpar3 mouse. situation, primarily mechanopruriceptive sensors selected pruritogens. NHPs, expression, broader compounds, share described below. 9. C-pruriceptor (chemo) NP2-type occasionally wrapping follicles.25,37,156 cold,37 4% 7% neurons.25,155 itch,37 suggest (see below). show one.114,131,151 dete

Language: Английский

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Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine‐Independent and Chronic Itch

Advanced Science, Journal Year: 2024, Volume and Issue: 11(15)

Published: Feb. 13, 2024

Abstract Various disorders are accompanied by histamine‐independent itching, which is often resistant to the currently available therapies. Here, it reported that pharmacological activation of Slack (Kcnt1, K Na 1.1), a potassium channel highly expressed in itch‐sensitive sensory neurons, has therapeutic potential for treatment itching. Based on Slack‐activating antipsychotic drug, loxapine, series new derivatives with improved pharmacodynamic and pharmacokinetic profiles designed enables validate as target vivo. One these activators, compound 6, exhibits negligible dopamine D 2 3 receptor binding, unlike loxapine. Notably, 6 displays potent on‐target antipruritic activity multiple mouse models acute chronic itch without motor side effects. These properties make lead molecule development therapies targeting Slack.

Language: Английский

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Risks of cutaneous immune‐related adverse events in long COVID: Multinational cohort studies in South Korea, Japan, and the UK

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(6)

Published: June 1, 2024

Previous research has not investigated the persistent cutaneous immune-related adverse events (cirAEs) related to long COVID investigate long-term sequelae. This multinational study, using a propensity-matched overlap weighting method, utilizes large national claims-based cohorts, ICD-10 code diagnosis, focusing on patients aged ≥20 years from three countries: South Korean, Japanese, and British cohorts. To estimate risk of cirAEs in COVID, persistence or emergence occurring 4 weeks after initial SARS-CoV-2 infection, we employed Cox proportional hazard regression model. The Korean cohort (n = 5,937,373; mean age 49.2 [SD: 13.2]), Japanese 4,307,587; 42.5 [13.6]), UK 395,435; 71.0 [8.07]) were presented. An increased was observed (HR, 1.10; 95% CI, 1.06-1.14) cohort, while similar association higher more severe COVID-19 cases (1.31; 1.22-1.39). Unlike vaccination attenuated risk, especially with two doses (1.03; 0.95-1.11) heterologous regimens (0.98; 0.76-1.27). time attenuation effect indicated sustained for up 6 months postinfection (<3 months: 1.13 [1.07-1.19]; 3-6 1.14 [1.06-1.22]). infection is associated an aspect COVID. Vaccination might reduce this highlighting need preventive strategies management.

Language: Английский

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Kappa opioids inhibit spinal output neurons to suppress itch

Science Advances, Journal Year: 2024, Volume and Issue: 10(39)

Published: Sept. 25, 2024

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca 2+ imaging of dorsal horn visualize neuronal populations are activated by itch-inducing agents. We identify convergent population spinal interneurons recruited diverse itch-causing stimuli represents subset neurons express gastrin-releasing peptide receptor (GRPR). Moreover, find conveyed brain via GRPR-expressing output target lateral parabrachial nuclei. then show kappa opioid agonist nalfurafine relieves selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide population-level view respond pruritic stimuli, pinpoint convey brain, and cellular agonists inhibition itch.

Language: Английский

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Cytokines reprogram airway sensory neurons in asthma

Cell Reports, Journal Year: 2024, Volume and Issue: 43(12), P. 115045 - 115045

Published: Dec. 1, 2024

Language: Английский

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Evaluation, management and future perspectives of anal pruritus: a narrative review

European journal of medical research, Journal Year: 2023, Volume and Issue: 28(1)

Published: Feb. 2, 2023

Abstract Purpose The without a time limitation. Most recent search was performed on 1st June 2022. Results Thorough history and physical examination are very important in view of multiple possible causes anal pruritus. the focus during is drawn to perianal region. A digital rectal an anoscopy essential. It necessary aim this narrative review overview classification, diagnostics, treatment options future perspective Methods by two authors (AD MJ) independently following electronic databases: PubMed, EMBASE, Web Science, Cochrane Library, CENTRAL Allied Complementary Medicine Databases (AMED). Search restricted English language only avoid moisture use soaps Furthermore, patient should certain foods increase intake fiber. If symptoms do not resolve, topical steroids, capsaicin (0.006%) tacrolimus (0.1%) ointments may be used. For intractable cases, intradermal methylene blue injection might give long-lasting symptom relief. Conclusion Anal pruritus long-term deteriorating quality life issue. it with difficult diagnosis. for best treatment.

Language: Английский

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Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 152(4), P. 927 - 932

Published: July 13, 2023

Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD).

Language: Английский

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IL-13 promotes sensory-sympathetic neurons crosstalk in asthma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 27, 2023

Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential dangers environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors contribute immune cell infiltration, bronchial hypersensitivity, mucus imbalance, addition causing pain coughing. Despite this, specific mechanisms which acquire pro-inflammatory characteristics reactions are not yet fully understood. In study, we aimed investigate molecular profile of airway nociceptor inflammation identify signals driving such reprogramming. Using retrograde tracing lineage reporting, identified unique class inflammatory that exclusively innervate airways. ovalbumin mouse model inflammation, these undergo significant reprogramming characterized upregulation NPY receptor

Language: Английский

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