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Piezo1-Dependent Neuro-Immune Signaling in Macrophages Drives Colitis-Associated Visceral Pain [scRNA-Seq]

ABSTRACT: Visceral pain is a hallmark symptom of ulcerative colitis, yet its underlying mechanisms remain poorly defined. While neuro-immune interactions have been implicated in somatic pain, the contribution of specific immune cell subsets to colitis-associated visceral hypersensitivity is unclear. Here, we identify the mechanosensitive ion channel Piezo1 in CX3CR1+ resident macrophages as a key regulator of visceral pain in a murine model of dextran sulfate sodium (DSS)-induced colitis. Single-cell RNA sequencing and functional assays revealed that Piezo1 is upregulated and functionally active in both resident and infiltrating macrophages during colitis. However, conditional deletion of Piezo1 in CX3CR1+ resident macrophages, but not in CCR2+ infiltrating macrophages, markedly attenuated visceral hypersensitivity and alleviated colonic inflammation. Mechanistically, Piezo1 activation induced NGF expression in resident macrophages, which engaged TrkA signaling to promote sensory nerve remodeling and visceral pain. Genetic ablation of NGF in CX3CR1+ macrophages or TrkA in TRPV1+ sensory neurons recapitulated the analgesic effects. Together, these findings define a mechanosensory neuro-immune axis wherein Piezo1-expressing resident macrophage promotes nociceptor sensitization via NGF-TrkA signaling, highlighting Piezo1 as a potential therapeutic target for visceral pain in colitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE329447 | GEO | 2026/08/22

REPOSITORIES: GEO

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Piezo1-Dependent Neuro-Immune Signaling in Macrophages Drives Colitis-Associated Visceral Pain

Project description:Visceral pain is a hallmark symptom of ulcerative colitis, yet its underlying mechanisms remain poorly defined. While neuro-immune interactions have been implicated in somatic pain, the contribution of specific immune cell subsets to colitis-associated visceral hypersensitivity is unclear. Here, we identify the mechanosensitive ion channel Piezo1 in CX3CR1+ resident macrophages as a key regulator of visceral pain in a murine model of dextran sulfate sodium (DSS)-induced colitis. Single-cell RNA sequencing and functional assays revealed that Piezo1 is upregulated and functionally active in both resident and infiltrating macrophages during colitis. However, conditional deletion of Piezo1 in CX3CR1+ resident macrophages, but not in CCR2+ infiltrating macrophages, markedly attenuated visceral hypersensitivity and alleviated colonic inflammation. Mechanistically, Piezo1 activation induced NGF expression in resident macrophages, which engaged TrkA signaling to promote sensory nerve remodeling and visceral pain. Genetic ablation of NGF in CX3CR1+ macrophages or TrkA in TRPV1+ sensory neurons recapitulated the analgesic effects. Together, these findings define a mechanosensory neuro-immune axis wherein Piezo1-expressing resident macrophage promotes nociceptor sensitization via NGF-TrkA signaling, highlighting Piezo1 as a potential therapeutic target for visceral pain in colitis.

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Piezo1-Dependent Neuro-Immune Signaling in Macrophages Drives Colitis-Associated Visceral Pain

Project description:Piezo1-Dependent Neuro-Immune Signaling in Macrophages Drives Colitis-Associated Visceral Pain

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Piezo1-Dependent Neuro-Immune Signaling in Macrophages Drives Colitis-Associated Visceral Pain [scRNA-Seq]

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PIEZO1 activation and signalling is associated with inflammation permissive phenocopy of synovial resident macrophages in early arthritis

Project description:Synovial resident macrophages in humans play a key role in maintaining tissue and synovial fluid homeostasis and typically exhibit protective phenotypes. However, at the start of rheumatoid arthritis, macrophages can adopt inflammation-permissive phenotypes. The factors that influence macrophage phenotype during the early stages of arthritis are not yet fully understood. Interestingly, in mice, mechanical stress is required for the localization of joint inflammation. Given the critical roles of macrophages, we investigated whether mechanosensation contributes to the regulation of macrophage phenotypes. PIEZO1, a well-established mechanosensor expressed on macrophages, regulates various macrophage functions, including migration and phagocytosis. We found that PIEZO1 activation in macrophages shifted their phenotype to a tissue-resident (MERTKhigh, CD36high), inflammation-permissive phenocopy (TREM2low, VSIG4low), with elevated MHC class II and cytokine secretion. Additionally, in vivo activation of PIEZO1 in mice produced similar effects in synovial tissue macrophages (STMs) and led to increased recruitment of monocytes and neutrophils. By dissecting the PIEZO1 signalling pathway, we were able to restore the protective macrophage phenotype by inhibiting calpain signalling and knocking-out HIF1α, both downstream mediators of PIEZO1 activation. Furthermore, we observed that PIEZO1 expression is present in synovial macrophages from patients with active rheumatoid arthritis and decreases during remission, suggesting a link between macrophage PIEZO1 expression and disease activity

2026-01-31 | E-MTAB-15203 | biostudies-arrayexpress

PIEZO1 activation and signalling is associated with inflammation permissive phenocopy of synovial resident macrophages in early arthritis

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Fingerprinting of the hNGF P61R100E gene expression in rat Dorsal Root Ganglion detected by microarray analysis

Project description:Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment, not merely as a long-lasting cholinergic maintainer and neuroprotective agent but also as a direct anti-amyloidogenic factor. However, the development of a NGF-based therapy for neurodegenerative diseases is limited by the partial access of NGF to the brain and to its potent nociceptive actions in animals and humans. Indeed, NGF is involved in pain transmission and perception. The nociceptive activity of NGF is mediated through the activation of TrkA and p75NTR receptors on sensory nerve endings. Our group recently studied forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. This “painless” hNGF hNGFP61S/R100E displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo, via a selective alteration of TrkA versus p75NTR binding and signaling. The molecular mechanism through which pNGF reduces nociceptive activity has never been investigated, therefore we performed gene expression microarray analysis to investigated the effect of hNGF hNGFP61S/R100E delivery in rat Dorsal Root Ganglia.

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