4.5 Article

SPP1 exacerbates ARDS via elevating Th17/Treg and M1/M2 ratios through suppression of ubiquitination-dependent HIF-1α degradation

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CYTOKINE
卷 164, 期 -, 页码 -

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ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2022.156107

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ARDS; SPP1; HIF-1?; Th17; Treg; Macrophage; Degradation

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ARDS is a severe inflammatory pulmonary condition associated with the imbalance of Th17/Treg and M1/M2. Understanding the regulation of this balance may lead to novel therapeutic targets for ARDS.
Background: Acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary condition that leads to respiratory failure. The imbalance of Th17/Treg and M1/M2 is implicated in ARDS. A better understanding of the regulation of the balance of Th17/Treg and M1/M2 may provide novel therapeutic targets for ARDS. Methods: Plasma and BALF samples were collected from ARDS patients. Inflammatory cytokines were examined by ELISA. Th17, Treg, M1 and M2 were identified via immunofluorescence staining of ROR gamma t, Foxp3, iNOS and Arg-1. H&E and Masson's trichrome staining were applied for evaluating pulmonary damage and fibrosis. A mouse model of ARDS was established through LPS administration. HIF-1 alpha was immunoprecipitated and subjected to ubiquitination analysis via western blotting. The expression of SPP1, VHL and HIF-1 alpha was examined by RT-qPCR and western blotting.Results: ARDS patients showed elevated levels of inflammatory cytokines and ratios of Th17/Treg and M1/M2. SPP1 was upregulated in ARDS mice, and silencing of SPP1 alleviated lung injury and fibrosis. SPP1 inhibited VHL expression to reduce the ubiquitination and degradation of HIF-1 alpha in ARDS. Overexpression of SPP1 facilitated Th17, Treg and M1 polarization but inhibited M2 polarization through upregulation of HIF-1 alpha.Conclusion: SPP1 elevates Th17/Treg and M1/M2 ratio by suppressing VHL expression and ubiquitinationdependent HIF-1 alpha degradation, thus exacerbating ARDS. Our study provides novel mechanistic insights into ARDS pathogenesis and promising therapeutic targets.

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