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The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE253063 | GEO | 2024/02/21

REPOSITORIES: GEO

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The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

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 | GSE253041 | GEO

Nociceptive nerves regulate haematopoietic stem cell mobilization

Project description:Nociceptive neuropeptide CGRP acts directly on HSCs via the its receptor RAMP1/CALCRL, to promote egress by activating Gαs/Adenylyl cyclase/cAMP pathway.

2020-10-12 | GSE156449 | GEO

Bacteria hijack a neuro-immune axis in meninges to facilitate brain invasion

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.

2022-12-23 | GSE221681 | GEO

CGRP sensory neurons promote tissue healing by modulating neutrophils and macrophages

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

Mechanosensitive proteins are sensitized in myelinated afferents following in vivo inflammation

Project description:Here we identified two populations of myelinated sensory neurons that display markedly different phenotypes in terms of their action potential characteristics and responses to mechanical stimuli based on their expression of Calcitonin Gene-Related Peptide (CGRP). Myelinated neurons that did not express CGRP responded to mechanical stimuli with significantly larger currents during whole-cell voltage clamp recordings than their CGRP-positive counterparts, regardless of whether these neurons projected to the dorsal hindpaw skin or the gastrocnemius muscle. Importantly, this discrepancy could not be explained by a differential expression of mechanosensitive or mechanically-gated proteins like Stoml3 or Piezo2. Following inflammation of the skin or muscle, myelinated neurons demonstrated a sensitization to mechanical stimuli characterized by increased current amplitudes. Interestingly, myelinated neurons expressing CGRP are sensitized to mechanical stimuli following cutaneous inflammation of the paw, while myelinated neurons that do not express CGRP are sensitized to mechanical stimuli following inflammation of the gastrocnemius muscle. Microarray data was obtained from these populations by first using Fluorescence-Activated Cell Sorting (FACS) to separate the populations of interest. 15 different samples were analyzed, 3 biological replicates for each group (5 groups: saline paw-injected, CFA paw-injected, saline muscle-injected, acid muscle-injected, and CFA muscle-injected). The saline injected groups (paw and muscle) are considered controls.

2015-11-06 | E-GEOD-65613 | biostudies-arrayexpress

Calcitonin gene related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses

Project description:Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide CGRP (Calcitonin Gene-Related Peptide) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production and exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

2019-10-08 | GSE136154 | GEO

A chemogenetic screen for neuro-immune interactions in the gut: Trpv1+ nociceptor neurons control T regulatory cells

Project description:Neuroimmune crosstalk is critical for intestinal and tissue homeostasis. Yet the role of molecularly distinct subsets of gut-innervating neurons in regulating the activity of gut immunocytes, and the mechanisms of this neuroimmune signaling remain unclear. Here, we performed a chemogenetic and flow cytometry-based analysis of mice targeting eight different peripheral neuron subsets to assess how gut immunocytes are altered following neural activation. We found that distinct neurons modulated discreet anatomical populations of immunocytes in the gut in ileum, cecum, and colon. Nos1+ neuron activation decreased the percentage of RORg+ ileal conventional CD4+ T cells, whereas ChAT+ neuron activation decreased ileal neutrophils. Trpv1+ neuron activation displayed the most robust immunomodulatory phenotype, causing downregulation of RORg+ T regulatory cells in the colon and cecum. The immune cells exhibited decreased proliferation, enhanced cell stress, and altered cell activation markers. Further genetic and pharmacological approaches showed that spinal afferent Trpv1+ neurons specifically decreased Treg cells by signaling via the neuropeptide CGRP. Our study provided a comprehensive understanding of neuro-immune interactions, revealing a role for mechanisms by which Trpv1+ neurons regulate gut Treg cells.

2024-04-01 | GSE240982 | GEO

Neuropeptide CGRP limits ILC2 responses and constrains type 2 inflammation

Project description:Innate and adaptive lymphocytes work in concert to maintain tissue homeostasis and to mediate host defense at mucosal barriers. Herein, we used single cell analysis to show substantial diversity of gene expression in ILCs and T helper cells during a helminth infection in the lung. Notably, we found that the Calca gene, which is spliced to generate the neuropeptide CGRP, was selectively transcribed in ILC2s and Th2 cells in an activation dependent manner. The Calca locus acquired chromatin accessibility at the ILC2 precursor stage and is pre-programmed for rapid production of CGRP upon ILC2 activation. CGRP globally antagonized actions of neuromedin U (NMU) and the alarmin IL-33. However, CGRP selectively acted in concert with NMU and IL-33 to promote IL-5 expression, but not IL-13. The complex interplay among neuropeptides and alarmin fine-tunes type 2 immune responses and will undoubtedly become more relevant as therapeutic neuropeptide blockade advances in the clinic.

2019-06-25 | GSE131996 | GEO

Mechanosensitive proteins are sensitized in myelinated afferents following in vivo inflammation

2015-11-06 | GSE65613 | GEO

Expression Data from fracture calli of alpha-CGRP deficient mice

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

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