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Nppb Neurons Are Sensors Of Mast Cell-Induced Itch

ABSTRACT: Itch is an unpleasant skin sensation which can be triggered by exposure to many chemicals including those released by mast cells. The Nppb-expressing class of sensory neurons when activated elicit scratching responses in mice, however, it is unclear which itch-inducing agents stimulate these cells and the receptors involved. Here, we identify receptors expressed by Nppb-neurons and demonstrate the functional importance of these receptors as sensors of endogenous pruritogens released by mast cells. Our search for receptors in Nppb-neurons revealed that they express leukotriene, serotonin, and sphingosine-1-phosphate receptors. Targeted cell ablation, calcium imaging of primary sensory neurons, and conditional receptor knockout studies demonstrate that these receptors induce itch by the direct stimulation of Nppb-neurons and neurotransmission through the canonical GRP-dependent spinal cord itch pathway. Together our results define a molecular and cellular pathway for mast cell-induced itch.

ORGANISM(S): Mus musculus

PROVIDER: GSE125626 | GEO | 2019/03/26

REPOSITORIES: GEO

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Nppb Neurons Are Sensors Of Mast Cell-Induced Itch

Project description:Nppb Neurons Are Sensors Of Mast Cell-Induced Itch

| PRJNA516935 | ENA

Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch [6 NaV1.8+ Il4raF/F mice treated with MC903 compared to skin from 4 littermates]

Project description:Mammals have evolved neurophysiologic reflexes such as coughing and scratching to expel invading pathogens and noxious environmental factors. It is well established that these responses are also associated with chronic inflammatory diseases such as asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly stimulate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. Based on these observations, we show that patients with recalcitrant chronic itch markedly improve when treated with JAK inhibitors in proof-of-concept clinical studies. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, these studies reveal an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

2017-09-18 | GSE100397 | GEO

Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch

Project description:Mammals have evolved neurophysiologic reflexes such as coughing and scratching to expel invading pathogens and noxious environmental factors. It is well established that these responses are also associated with chronic inflammatory diseases such as asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that the type 2 cytokines IL-4 and IL-13 directly stimulate sensory neurons and that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. In proof-of-concept clinical studies, we further show that patients with recalcitrant chronic itch markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, these studies reveal an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

2017-09-18 | GSE90883 | GEO

Molecular signature of pruriceptive MrgprA3+ neurons

Project description:We performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis conditions. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are a direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

2020-03-13 | GSE146876 | GEO

IL-33-activated calcitonin gene-related peptide-producing memory Th2 cells co-operate with somatosensory neurons to induce conjunctival itch

Project description:Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva; but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.

2022-05-20 | GSE203217 | GEO

Transcriptional regulation of human dorsal root ganglia cultures by type 2 cytokines

Project description:Cutaneous afferent neurons express receptors for type 2 cytokines, including interleukins (IL)-4, IL-13, and IL-33. These neuronal cytokine receptors were found to be required in several murine models of itch. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Human dorsal root ganglia were isolated and dissociated to establish ex vivo cultures and subjected to 24 hours of type 2 cytokine exposure with either vehicle, IL-4, IL-13, IL-33, or IL-4 and IL-13 together. After 24 hours, cells were harvested and RNA extracted and sequenced to determine the transcriptomic effects of type 2 cytokine exposure.

2023-09-22 | GSE242488 | GEO

Identification of a regulatory domain controlling the Nppa-Nppb gene cluster during heart development and stress

Project description:The paralogous genes Nppa and Nppb are organized in an evolutionary conserved cluster and are a valuable model to study coregulation and regulatory landscape organization during heart development and disease. Here, we analyzed the chromatin conformation, epigenetic status and enhancer potential of sequences of the Nppa-Nppb cluster in vivo. Our data indicate that the regulatory landscape of the cluster is present within a 60 kbp domain centered around Nppb. Both promoters and several potential regulatory elements interact with each other in a similar manner in different tissues and developmental stages. The distribution of H3K27ac and the association of Pol2 across the locus changed during cardiac hypertrophy, revealing their potential involvement in stress-mediated gene regulation. In summary, the developmental regulation and stress-response of the Nppa-Nppb cluster involve the concerted action of multiple enhancers and epigenetic changes distributed across a structurally rigid regulatory domain. We have used 4C-seq on several viewpoints around the Nppa-Nppb gene cluster in the heart and liver samples to investigate the role of chromatin conformation on regulation of Nppa and Nppb expression during heart development and disease.

2016-07-02 | E-GEOD-81057 | biostudies-arrayexpress

Transcriptional characterization of LV of Nppb KO

Project description:Expression analysis of LV in Nppb KO

2019-07-22 | GSE128196 | GEO

RNA-seq of primary human keratinocytes and primary mouse trigeminal ganglion neurons: Effects of IL-27 and BST2 on gene expression

Project description:In the present study, RNA-seq were performed To explore biological significance of IL-27 and BST2 in the neuro-cutaneous signaling network of chronic itch. mRNA profiles were generated by deep sequencing, in triplicate, using MGISEQ-2000. We found that both human keratinocytes and murine sensory neurons responded to IL-27 and BST2, resulting in enrichment of genes promoting itch and inflammation. IL-27-BST2 signaling pathway activation promotes cutaneous inflammation and itch, both leading into an aggravation of AD. This finding might help us to better understand the immune-neuro-modulatory mechanism in itch circuits

2024-03-05 | GSE188242 | GEO

DNA methylation in Prurigo Nodularis

Project description:Prurigo nodularis is a debilitating skin condition that is characterized by chronic itch and a prolonged scratching behavior. Little is known of the underlying molecular mechanisms that initiate and maintain the desease. Therefore, we analyzed DNA methylation in prurigo patients and matched healthy controls.

2022-10-31 | GSE210852 | GEO

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