Neuroimmune communication regulating pruritus in atopic dermatitis

Journal of Allergy and Clinical Immunology, Год журнала: 2022, Номер 149(6), С. 1875 - 1898

Опубликована: Март 23, 2022

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system immune system. Dysregulation neuroimmune circuits plays key role in pathophysiology causing inflammation, pruritus, pain, barrier dysfunction. Sensory nerves can be activated by or endogenous factors, transmitting itch stimuli brain. On stimulation, sensory nerve endings also release neuromediators into skin, contributing again dysfunction, itch. In addition, dysfunctional peripheral central neuronal structures neuroinflammation, sensitization, elongation, neuropathic itch, thus chronification therapy resistance. Consequently, may targets treat pruritus AD. Cytokines, chemokines, proteases, lipids, opioids, ions excite/sensitize endings, which not only induces but further aggravates/perpetuates disruption, as well. Thus, targeted therapies for well pathway inhibitors (eg, kinase inhibitors) beneficial control AD either systemic and/or topical form. Understanding signaling will optimize approach all pathological mechanisms pruritus.

Язык: Английский

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Basic mechanisms of itch

Journal of Allergy and Clinical Immunology, Год журнала: 2023, Номер 152(1), С. 11 - 23

Опубликована: Май 17, 2023

Язык: Английский

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Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(6)

Опубликована: Фев. 1, 2023

Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch pathological conditions mice. Thus, GRPR could be an attractive target for cancer therapy. Here, we report inactive state crystal structure human complex with non-peptide antagonist PD176252, as well two active cryo-electron microscopy (cryo-EM) structures bound to endogenous agonist gastrin-releasing synthetic BBN analog [D-Phe6, β-Ala11, Phe13, Nle14] Bn (6-14), Gq heterotrimers. These revealed molecular mechanisms ligand binding, activation, proteins signaling GRPR, which are expected accelerate structure-based design antagonists agonists treatments pruritus.

Язык: Английский

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Representation and control of pain and itch by distinct prefrontal neural ensembles

Neuron, Год журнала: 2023, Номер 111(15), С. 2414 - 2431.e7

Опубликована: Май 23, 2023

Язык: Английский

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Molecular and neural basis of pleasant touch sensation

Science, Год журнала: 2022, Номер 376(6592), С. 483 - 491

Опубликована: Апрель 28, 2022

Pleasant touch provides emotional and psychological support that helps mitigate social isolation stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch–conditioned place preference (PT-CPP) test, we show genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain itch behaviors mice. Mutant mice display profound impairments stress response prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking encode reward value. Collectively, identify as long-sought neuropeptide encodes transmits neurons. These findings may have important implications for elucidating by which deprivation contributes avoidance behavior mental disorders.

Язык: Английский

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An atlas of neuropathic pain-associated molecular pathological characteristics in the mouse spinal cord

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Янв. 17, 2025

Peripheral nerve injury (PNI)-induced neuropathic pain (NP) is a severe disease with high prevalence in clinics. Gene reprogramming and tissue remodeling the dorsal root ganglia (DRG) spinal cord (SC) drive development maintenance of (NP). However, our understanding NP-associated spatial molecular processing landscape SC non-synaptic interactions between DRG neurons cells remains limited. We here integrate transcriptomics (ST) single-nucleus RNA-sequencing (snRNA-seq) bulk (bulk RNA-seq) to characterize regional pathological heterogeneity under NP conditions. First, mice manifests unique atlases genes, cell populations, cell-cell cross-talks, signaling pathways, transcriptional regulatory networks compared sham mice. further report that injured sensory corresponding ventral horn show similar expression patterns after PNI. In addition, for first time, we systematically exhibit "cross-talk omics" glial cells, indicating an altered communication profile Together, findings decode cellular mechanisms underlying NP, providing foundation designing therapeutic targets this disorder.

Язык: Английский

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Downregulation of the NPY-Y1R system in Grpr neurons results in mechanical and chemical hyperknesis in chronic itch

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106806 - 106806

Опубликована: Янв. 1, 2025

Язык: Английский

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Chronic Nodular Prurigo: An Update on the Pathogenesis and Treatment

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(20), С. 12390 - 12390

Опубликована: Окт. 16, 2022

Chronic nodular prurigo (CNPG) is a recalcitrant chronic itchy disorder that affects the quality of life. It can be triggered by multiple etiologies, such as atopic dermatitis, diabetes, and renal diseases. The mechanisms CNPG are complicated involved interaction cutaneous, immune, nervous systems. Diverse immune cells, including eosinophils, neutrophils, T macrophages, mast cells infiltrated lesional skin CNPG, which initiated inflammatory cytokines pruritogens release. In addition, between activated peripheral sensory nerve fibers neurotransmitters caused neuroinflammation in intractable itch. This itch-scratch vicious cycle results disease exacerbation. difficult to treat with traditional therapies. Recently, great advances have been made pathophysiology both inflammation pruritus transmission CNPG. this review, we summarize updated novel therapies for

Язык: Английский

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Microglia–neuron interactions promote chronic itch via the NLRP3‐IL‐1β‐GRPR axis

Allergy, Год журнала: 2023, Номер 78(6), С. 1570 - 1584

Опубликована: Март 6, 2023

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

Язык: Английский

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Beyond the classic players: Mas‐related G protein‐coupled receptor member X2 role in pruritus and skin diseases

Journal of the European Academy of Dermatology and Venereology, Год журнала: 2024, Номер unknown

Опубликована: Июль 23, 2024

Abstract Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune environmental factors. Recent advancements in the field have demonstrated key role mast cells (MC) these conditions. The Mas‐related G protein‐coupled receptor X2 (MRGPRX2) has emerged as promising non‐IgE‐mediated MC activation receptor. MRGPRX2 predominately expressed activated by endogenous exogenous ligands, leading to degranulation release various pro‐inflammatory mediators. Mounting evidence presence agonists (substance P, cortistatin‐14, LL37, PAMP‐12 VIP) its high expression among patients with CSU, AD, rosacea, chronic pruritus emphasizes pathogenic Despite currently available treatments, there remains pressing need for novel drug targets treatment options Here, we reviewed potential therapeutic target provided an update future research directions.

Язык: Английский

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