Ontology highlight
ABSTRACT:
PROVIDER: PRJNA803622 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18158500_1.fastq.gz | Fastqsanger.gz | |||
| SRR18158500_2.fastq.gz | Fastqsanger.gz | |||
| SRR18158501_1.fastq.gz | Fastqsanger.gz | |||
| SRR18158501_2.fastq.gz | Fastqsanger.gz | |||
| SRR18158502_1.fastq.gz | Fastqsanger.gz |
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Project description:The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.
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Project description:Endometriosis is a debilitating and painful gynecological inflammatory disease affecting approximately 15% of women. Current treatments are ineffective for a significant fraction of patients, underscoring the need for new medical therapies with long-term benefits. Given the relevance of neuroimmune communication in different disease outcomes, we investigated the role of CGRP-mediated neuroimmune communication in endometriosis. We found that mouse and human endometriosis lesions contained CGRP and RAMP1. In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptor activation and neuropeptide release contribute to endometriosis lesion growth and pain. In vitro, CGRP-induced pro-endometriosis macrophages (PEMs) showed impaired efferocytosis and supported endometrial cell growth in a RAMP1-dependent manner. Treatment with FDA-approved drugs that block CGRP-RAMP1 signaling reduced mechanical hyperalgesia, spontaneous pain, and lesion size in mice. Altogether, our data demonstrates the effectiveness, cellular mechanisms and pre-clinical safety of non-hormonal and non-opioid CGRP/RAMP1 blocking therapies, which may lead to clinical benefit for endometriosis patients.
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Project description:The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.
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Project description:Pain, detected by nociceptors, is an integral part of injury, yet whether and how it can impact tissue physiology and recovery remain understudied. Here we applied chemogenetics in mice to locally activate dermal TRPV1 innervations in naïve skin and found it triggered new regenerative cycling by dormant hair follicles (HFs).This was preceded by rapid apoptosis of dermal macrophages, mediated by the neuropeptide calcitonin gene-related peptide (CGRP). TRPV1 activation also triggered a macrophage-dependent induction of Spp1-expressing dermal fibroblasts. The neuropeptide CGRP andSpp1were essential for the nociceptor-triggered hair growth. Finally, we show that epidermal abrasion injury induced Spp1-expressing dermal fibroblasts and hair growth via a TRPV1 neuron and CGRP dependent mechanism.Collectively, these data demonstrate a role for TRPV1 nociceptors in orchestrating a macrophage and fibroblast-supported mechanism to promote hair growth, and enabling the efficient restoration of this mechano- and thermo-protective barrier after wounding.
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Project description:Pain, detected by nociceptors, is an integral part of injury, yet whether and how it can impact tissue physiology and recovery remain understudied. Here we applied chemogenetics in mice to locally activate dermal TRPV1 innervations in naïve skin and found it triggered new regenerative cycling by dormant hair follicles (HFs).This was preceded by rapid apoptosis of dermal macrophages, mediated by the neuropeptide calcitonin gene-related peptide (CGRP). TRPV1 activation also triggered a macrophage-dependent induction of Spp1-expressing dermal fibroblasts. The neuropeptide CGRP andSpp1were essential for the nociceptor-triggered hair growth. Finally, we show that epidermal abrasion injury induced Spp1-expressing dermal fibroblasts and hair growth via a TRPV1 neuron and CGRP dependent mechanism.Collectively, these data demonstrate a role for TRPV1 nociceptors in orchestrating a macrophage and fibroblast-supported mechanism to promote hair growth, and enabling the efficient restoration of this mechano- and thermo-protective barrier after wounding.
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Project description:The colon is densely innervated by nociceptor neurons. Single cell RNA sequencing (scRNA-seq) of colon epithelial cells was performed to analyze the role of nociceptor neurons and Ramp1 signaling in regulating colonic epithelial cells.
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