CGRP sensory neurons promote tissue healing by modulating neutrophils and macrophages
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ABSTRACT:
PROVIDER: PRJNA1073432 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27871666.fastq.gz | Fastqsanger.gz | |||
| SRR27871667.fastq.gz | Fastqsanger.gz | |||
| SRR27871668.fastq.gz | Fastqsanger.gz | |||
| SRR27871669.fastq.gz | Fastqsanger.gz | |||
| SRR27871670.fastq.gz | Fastqsanger.gz |
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Project description:Since the immune system plays a critical role in orchestrating tissue healing, regenerative strategies that control immune components have proven effective. This is particularly relevant when immune dysregulation resulting from conditions such as diabetes or advanced age impairs tissue healing following injury. Nociceptive sensory neurons play a crucial role as immunoregulators, exerting both protective and harmful effects depending on the context. However, how neuro-immune interactions impact tissue repair and regeneration after acute injury is unclear. Here, we show that Nav1.8+ nociceptor ablation impairs skin wound repair and muscle regeneration after acute tissue injuries. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity modifying protein 1 (RAMP1) on neutrophils and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis, and polarise macrophages towards a pro-repair phenotype. CGRP effects on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine/paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivering an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions holds potential to treat non-healing tissues where dysregulated neuro-immune interactions impair tissue healing.
2024-02-18 | GSE255049 | GEO
Project description:Bone healing is a tightly orchestrated, multiphase process that requires coordinated interactions between immune cells and skeletal cells. Sensory nerves act as intrinsic effectors of the inflammatory response, whose role in osteoimmunology during healing remains poorly defined. Using a bone healing model with sensory denervation, it’s shown that sensory nerves protect bone repair by suppressing excessive osteoclastogenesis. During the acute inflammatory phase, sensory nerves are upstream regulators of macrophage activation. At the molecular level, calcitonin gene-related peptide (CGRP), a sensory neuron–derived neuropeptide, is identified to modulate macrophage activation by restricting key functions such as migration, phagocytosis, and pro-inflammatory cytokine production. Importantly, CGRP rapidly constrains adenosine triphosphate (ATP) synthesis with limited mitochondrial respiration in activating macrophages, accompanied by downregulating genes associated with oxidative phosphorylation and mitochondrial complex components. Following the metabolic checkpoint, macrophages exposed to CGRP show attenuated osteoclastogenic capacity, with decreased secretion of multiple key factors that support osteoclast differentiation and survival. Together, these findings indicate the neuro–immune–metabolic axis in bone healing, where sensory nerve–derived CGRP influences macrophage bioenergetics and thereby contributes to osteoimmunological regulation. It emphasizes the potential of incorporating sensory signals into therapeutic strategies, particularly those targeting immunometabolism in bone regeneration.
2026-03-01 | GSE314711 | GEO
Project description:Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, skewed tumor associated macrophage polarization, reduced tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multiomics analyses of human OS bone samples further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. Next and in two parallel approaches to inhibit nerve ingrowth, we repurposed FDA-approved bupivacaine liposomes and separately blocked CGRP signaling using FDA-approved Rimegepant. Both strategies led to significant reductions in sarcoma growth, vascularity, and sarcoma-induced hyperalgesia. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition disrupts CGRP signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of OS represent an adjunctive therapy to improve clinical outcomes and survival.
2025-01-04 | GSE252589 | GEO
Project description:alpha-CGRP is a neuropeptide that is also expressed in the fracture callus during bone regeneration. Our aim was to evaluate the role of alpha-CGRP in the context of fracture healing. Therefore we investigated the effect of alpha-CGRP deficiency on fracture callus formation. We used microarray analysis to compare the global gene expression of fracture calli from alpha-CGRP deficient mice and WT mice.
2020-09-02 | GSE148720 | GEO
Project description:Peripheral sensory nerves are thought to contribute to solid tumor growth, particularly in oral squamous cell carcinoma (OSCC); however, the link between pain and immunosuppression remains unresolved. Here, using a prospective observational study, we demonstrate an inverse relationship between OSCC-induced pain mediated by calcitonin gene-related peptide (CGRP)-expressing nerves and tumor-associated immunity. Bulk RNA sequencing of tumor-innervating sensory neurons from mice revealed differential regulation of genes associated with excitability, neurotransmission, and axonal sprouting. Using a gain-of-function approach with persistent stimulation of peptidergic afferents, we show that sensory neurons promote oral tongue tumor growth and limit the activation of effective anti-tumor immune responses via efferent CGRP release. Conversely, loss-of-function approaches—including local ablation of nociceptive nerves and systemic CGRP receptor antagonism—slowed tumor growth and improved anti-tumor immunity. Targeting CGRP may therefore represent a therapeutic strategy in OSCC to reduce pain and improve treatment response.
2026-01-19 | GSE315799 | GEO
Project description:The SETDB2/KLF4/IDE/CGRP signaling axis in sensory neurons controls migraine [NTG]
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Project description:Sensory nerve-derived CGRP controls osteoclastogenesis by limiting macrophage bioenergetics in bone repair
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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.
2024-02-21 | GSE253063 | GEO
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:A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association between muscle nerves, IL-33+ mSCs and Tregs has been reported, and begs a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down- tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell cross-talk in tissue repair, suggesting future therapeutic approaches.
2020-02-10 | GSE143424 | GEO