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Cutaneous nonpeptidergic neurons sense extracellular ATP to augment barrier repair and C. albicans host defense

ABSTRACT: Cutaneous pain-sensing nociceptive neurons can directly recognize pathogen invasion and modulate the resulting host immune response. Nociceptor recognition of C. albicans cell wall components is necessary and sufficient for optimal protective local Type-17 immune responses. We now report a parallel neuroimmune pathway in which extracellular ATP (eATP) released from C. albicans and keratinocytes activates nonpeptidergic neurons including Mrgprd-expressing NP1 neurons through the P2RX3 ATP receptor. Ablation of NP1 neuron or P2rx3 increased C. albicans CFU but the induction of Type-17 responses was unaffected. Rather, transcriptomic analysis revealed alteration in genes and pathways associated with barrier repair. P2rx3-/- mice showed increased wound size and transepidermal water loss associated with a delay in barrier repair following C. albicans infection or abrasion. These data reveal a novel pathway where nonpeptidergic neurons sense epidermal damage or infection through eATP and P2X3 resulting in augmented barrier repair and host defense.

ORGANISM(S): Mus musculus

PROVIDER: GSE329413 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Ectopic adenosine triphosphate synthase (eATP synthase) was found on the cell surface to generate extracellular ATP in various cancer cells. Recently using proteomics approach, several reports identified ATP synthase in extracellular vesicles (EVs) which are important in cell-cell communications. However, the functions of ATP synthase in EVs are still unclear. Here we increased the expression of eATP synthase on the plasma membrane of lung cancer A549 cells via 0.1% FBS starvation and collected EVs including microvesicles and exosomes from the culture medium using serial centrifugation. Both of them were assuredly isolated and confirmed by transmission electron microscopy, nano tracking analysis, and specific EV markers. We also used western blot to demonstrate the presence of ATP synthase in EVs. Besides, dot blot experiment revealed that the F1 portion faced towards extracellular space using anti-ATP beta subunit antibody. Under starvation, the expression of eATP synthase was enhanced on cell surface and exosomes as well as increased EV secretion. To further investigate the functions, we first elucidated whether eATP synthase on EV membrane produced ATP by ATP luciferase analysis. Our data showed that there was no significant ATP production. Moreover, we performed proteomic analysis using dimethyl labeling and LC-MS/MS to compare the difference between EVs released by A549 control and starvation. We identified a total of 1504 and 869 proteins in microvesicles and exosomes, respectively. Using 1.5- and 0.67-fold change as the thresholds, there were 171 and 46 differential expressed proteins in microvesicles and exosomes, respectively. Seven ATP synthase subunits in microvesicles and five in exosomes were identified. The proteomic data were further analyzed using gene set enrichment analysis (GSEA) within the C2 (curated gene sets) subclasses and setting 0.25 as FDR cutoff to find out biological functions related to eATP synthase. Among these up-regulated terms, metabolism, cell cycle and apoptosis were enriched, which indicating that starvation influences cell behavior. Additionally, the immune response is upregulated strikingly in exosomes within C2 gene set. One of these immune response pathways, MHC-1 antigen presentation, was previously proved to interact with eATP synthase which could be recognized by several immune cells.

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Cutaneous nonpeptidergic neurons sense extracellular ATP to augment barrier repair and C. albicans host defense

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