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Roquin-1 resolves sepsis-associated acute liver injury by regulating inflammatory profiles via miRNA cargo in extracellular vesicles.

ABSTRACT: Sepsis-associated acute liver injury (SALI) is an independent risk for sepsis-induced death orchestrated by innate and adaptive immune responses. Here, we found that Roquin-1 was decreased during SALI and expressed mainly in monocyte-derived macrophages. Meanwhile, Roquin-1 was correlated with the inflammatory profiles in humans and mice. Mechanically, Roquin-1 in macrophages promoted Ago2-K258-ubiquitination and inhibited Ago2-S387/S828-phosphorylation. Ago2-S387-phosphorylation inhibited Ago2-miRNA's complex location in multivesicular bodies and sorting in macrophages-derived extracellular vesicles (MDEVs), while Ago2-S828-phosphorylation modulated the binding between Ago2 and miRNAs by special miRNAs-motifs. Then, the anti-inflammatory miRNAs in MDEVs decreased TSC22D2 expression directly, upregulated Tregs-differentiation via TSC22D2-STAT3 signaling, and inhibited M1-macrophage-polarization by TSC22D2-AMPKα-mTOR pathway. Furthermore, WT MDEVs in mice alleviated SALI by increasing Tregs ratio and decreasing M1-macrophage frequency synchronously. Our study showed that Roquin-1 in macrophages increased Tregs-differentiation and decreased M1-macrophage-polarization simultaneously via miRNA in MDEVs, suggesting Roquin-1 can be used as a potential tool for SALI treatment and MDEVs engineering.

SUBMITTER: Zheng L

PROVIDER: S-EPMC10405074 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Roquin-1 resolves sepsis-associated acute liver injury by regulating inflammatory profiles via miRNA cargo in extracellular vesicles.

Zheng Lei L Ling Wei W Zhu Deming D Li Zhi Z Li Yousheng Y Zhou Haoming H Kong Lianbao L

iScience 20230712 8

Sepsis-associated acute liver injury (SALI) is an independent risk for sepsis-induced death orchestrated by innate and adaptive immune responses. Here, we found that Roquin-1 was decreased during SALI and expressed mainly in monocyte-derived macrophages. Meanwhile, Roquin-1 was correlated with the inflammatory profiles in humans and mice. Mechanically, Roquin-1 in macrophages promoted Ago2-K258-ubiquitination and inhibited Ago2-S387/S828-phosphorylation. Ago2-S387-phosphorylation inhibited Ago2- ...[more]

PMID: 37554446

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Project description:Current biomarkers of Fabry nephropathy lack sensitivity in detecting early kidney damage and do not predict progression of nephropathy. Urinary extracellular vesicles (uEVs) and their molecular cargo could reflect early changes in renal impairment as they are secreted by the cells lining the urinary tract. We aimed to conduct a proof-of-concept study to investigate whether analysis of uEV characteristics and expression of uEV-derived microRNAs (miRNAs) could be applicable in studies to predict the development and progression of nephropathy in Fabry disease. A total of 20 Fabry patients were divided into two groups, depending on the presence of nephropathy. Chronological urine samples collected during 10-year follow-up were used for uEVs isolation with size exclusion chromatography. Nanoparticle tracking analysis was used to determine concentration and size of uEVs. We evaluated the expression of five uEV-derived miRNAs by qPCR (miR-23a-3p, miR-29a-3p, miR-30b-5p, miR-34a-5p, miR-200a-3p). There was no difference in the concentration and size of uEVs between patients with and without nephropathy at last follow-up or longitudinally. However, we found increased expression of miR-29a-3p and miR-200a-3p in uEVs isolated from chronological samples of patients with Fabry nephropathy. This may indicate an attempt by the organism to prevent the progression of renal damage leading to end-stage renal disease as previously reported in type 1 diabetes. In addition, we found an increased expression of miR-30b-5p in the 10-year period in uEVs of patients without renal dysfunction. miR-30b-5 was reported to have a protective role in podocyte injury and may possibly be important in Fabry nephropathy. These findings indicate that uEVs and their molecular cargo could be a promising target of studies focusing on elucidation of Fabry nephropathy. Nevertheless, total concentration and size of uEVs were neither indicative of the presence nor progression of Fabry nephropathy, while the role of the analyzed miRNAs in Fabry nephropathy progression was merely indicated and needs further in-depth studies.

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Dataset Information

Roquin-1 resolves sepsis-associated acute liver injury by regulating inflammatory profiles via miRNA cargo in extracellular vesicles.

Publications

Roquin-1 resolves sepsis-associated acute liver injury by regulating inflammatory profiles via miRNA cargo in extracellular vesicles.

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