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Proteoglycofili are glycosaminoglycan-containing fibrillar components released by neutrophils to neutralize bacteria

ABSTRACT: Here we uncover that neutrophils release a previously unidentified fibrillar complex, named proteoglycofili (PGF) under hypoxic conditions or upon bacterial infection, using Shigella as a model. PGF are preferentially released by neutrophils over NETs upon bacterial infection. We demonstrated that PGF are released by living neutrophils, do not contain DNA and are mainly composed of granule proteins. We revealed that the fibrillar structure of PGF is sustained by two glycosaminoglycans (GAGs), hyaluronic acid and chondroitin sulfate, firstly identified here to be released by neutrophils. We demonstrated that PGF are potent antimicrobials, which degrade virulence factors of Shigella and block its growth, similarly with E. coli or Salmonella. We confirmed that GAGs were essential for PGF antimicrobial activity in vitro and in vivo. Beyond bacterial infections, our results strongly suggest that GAGs may be released by neutrophils in a broad range of inflammatory diseases to be further explored.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308441 | GEO | 2025/09/18

REPOSITORIES: GEO

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Project description:Background : In mucopolysaccharidosis type III (MPS III, also known as Sanfilippo syndrome), a pediatric neurodegenerative disorder, accumulation of abnormal glycosaminoglycans (GAGs) induces severe neuroinflammation by triggering the microglial pro-inflammatory cytokines production via a TLR4-dependent pathway. But the extent of the microglia contribution to the MPS III neuropathology remains unclear. Extracellular vesicles (EVs) mediate intercellular communication and are known to participate in the pathogenesis of adult neurodegenerative diseases. However, characterization of the molecular profiles of EVs released by MPS III microglia and their effects on neuronal functions have not been described. Methods : Here, we isolated EVs secreted by the microglial BV-2 cells after treatment with GAGs purified from urines of Sanfilippo patients (MPS-GAGs EVs) or from age-matched healthy subjects (WT-GAGs EVs) to explore the EVs’ proteins and small RNA profiles using LC–MS/MS and RNA sequencing. We next performed a functional assay by immunofluorescence following WT-GAGs- or MPS-GAGs-EVs uptake by WT primary cortical neurons and analyzed their extensions metrics after staining of βIII-tubulin and MAP2 by confocal microscopy. Results : Functional enrichment analysis for both proteomics and RNA sequencing data from MPS-GAGs-EVs revealed a specific content involved in neuroinflammation and neurodevelopment pathways. Treatment of cortical neurons with MPS-GAGs-EVs induced a disease-associated phenotype demonstrated by a lower total neurite surface area, an impaired somatodendritic compartment, and a higher number of immature dendritic spines. Conclusions : This study shows, for the first time, that GAGs from patients with Sanfilippo syndrome can induce microglial secretion of EVs that deliver a specific molecular message to recipient naive neurons, while promoting the neuroinflammation, and depriving neurons of neurodevelopmental factors. This work provides a framework for further studies of biomarkers to evaluate efficiency of emerging therapies.

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Proteoglycofili are glycosaminoglycan-containing fibrillar components released by neutrophils to neutralize bacteria

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