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The Functional Roles of RNAs Cargoes Released by Neutrophil-Derived Exosomes in Dermatomyositis

ABSTRACT: Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by cutaneous manifestations. We first identified the profiles of noncoding RNAs (lncRNAs and miRNAs) in peripheral neutrophil exosomes (EXOs) of DM patients and explored their potential functional roles. Bioinformatics analyses were performed with R packages. Real-time quantitative PCR was used to validate the altered RNAs in DM neutrophil EXO-stimulated human dermal microvascular endothelial cells (HDMECs) and human skeletal muscle myoblasts (HSkMCs). In DM neutrophil EXOs, 124 upregulated lncRNAs (with 1,392 target genes), 255 downregulated lncRNAs (with 1867 target genes), 17 upregulated miRNAs (with 2,908 target genes), and 15 downregulated miRNAs (with 2,176 target genes) were identified. GO analysis showed that the differentially expressed (DE) lncRNAs and DE miRNAs participated in interleukin-6 and interferon-beta production, skeletal muscle cell proliferation and development, and endothelial cell development and differentiation. KEGG analysis suggested that DE lncRNAs and DE miRNAs were enriched in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways. Many novel and valuable DE lncRNAs and DE miRNAs interacted and cotargeted in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways. Our study suggests that neutrophil EXOs participate in DM pathogenesis through lncRNAs and miRNAs in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155281 | GEO | 2021/09/17

REPOSITORIES: GEO

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Project description:Limbal stem cells including epithelial and stromal/Mesenchymal stem cells that contribute to sustained corneal homeostasis, maintain their ability to act as self-renewal progenitor cells by virtue of their limbal niche and intercellular communication. Extracellular vehicles (EVs), including exosomes (Exos), are important paracrine mediators through their cargo transfer for intercellular communication in various stem cell niches. Previously we have shown the differential cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos, in limbal epithelial cells (LEC) in normal (N) and diabetic (DM) limbal niche. In the present study, to have a comprehensive knowledge of reciprocal LEC-LSC crosstalk, we investigated the proteomics and miRNA profile of exosomes derived from LEC and their regulatory roles in LSC in N and DM limbus. Our study showed wound healing and proliferation rates in primary N-LSC were significantly enhanced upon treatment by normal LEC-derived Exos (N-Exos), but not by diabetic Exos (DM-Exos). Further, N-Exos treated LSC showed downregulation of keratocyte markers, ALDH3A1 and lumican, but not keratocan, and upregulation of MSC markers, CD105, CD90, and CD73 compared to the DM-Exos treated LSC. Using next generation sequencing (NGS) and proteomics analysis, we revealed some miRNAs and proteins in the Exos that affect the cellular crosstalk and the function of the cornea. We also documented differences in DM vs. normal LEC-derived Exo’s cargos. Overall, DM-Exos have less effect on LSC proliferation, wound healing, and stem cell maintenance than N-Exos, likely by transferring their cargo proteins and/or regulatory miRNAs targeting cell cycle, ERK/MAPK, TGF-β, EMT, PI3K-Akt-mTOR signaling molecules. This suggests that the small RNA and protein cargo differences in DM vs. N LEC-derived Exos could contribute to the disease state. Our study revealed a complex contribution of Exos to health and diabetic state of corneal homeostasis and suggests the potential of EV therapeutics for diabetic cornea regenerative medicine

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The Functional Roles of RNAs Cargoes Released by Neutrophil-Derived Exosomes in Dermatomyositis

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