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SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation

Wu et al., Frontiers in Immunology, doi:10.3389/fimmu.2023.1264447
Nov 2023  
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In Vitro and mouse study showing that quercetin may ameliorate COVID-19 associated acute kidney injury through modulation of macrophage polarization by blocking the Mincle/Syk/NF-kB pathway. Authors suggest that the SARS-CoV-2 N protein can exacerbate kidney injury in diabetic mice by promoting M1 proinflammatory macrophage activation via the Mincle-Syk/NF-kB pathway. Treatment with the flavonoid quercetin was found to inhibit N protein-induced acute kidney injury by suppressing Mincle signaling and switching macrophages from the M1 to M2 anti-inflammatory phenotype.
Wu et al., 3 Nov 2023, peer-reviewed, 12 authors.
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SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation
Wenjing Wu, Wenbiao Wang, Liying Liang, Junzhe Chen, Sifan Sun, Biao Wei, Yu Zhong, Xiao-Ru Huang, Jian Liu, Xiaoqin Wang, Xueqing Yu, Hui-Yao Lan
Frontiers in Immunology, doi:10.3389/fimmu.2023.1264447
Cytokine storm" is common in critically ill COVID-19 patients, however, mechanisms remain largely unknown. Here, we reported that overexpression of SARS-CoV-2 N protein in diabetic db/db mice significantly increased tubular death and the release of HMGB1, one of the damage-associated molecular patterns (DAMPs), to trigger M1 proinflammatory macrophage activation and production of IL-6, TNF-a, and MCP-1 via a Mincle-Syk/NF-kB-dependent mechanism. This was further confirmed in vitro that overexpression of SARS-CoV-2 N protein caused the release of HMGB1 from injured tubular cells under high AGE conditions, which resulted in M1 macrophage activation and production of proinflammatory cytokines via a Mincle-Syk/NF-kB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-a, and MCP-1 in vitro. Importantly, we also uncovered that treatment with quercetin largely improved SARS-CoV-2 N protein-induced AKI in db/db mice. Mechanistically, we found that quercetin treatment significantly inhibited the release of a DAMP molecule HMGB1 and inactivated M1 pro-inflammatory macrophage while promoting reparative M2 macrophage responses by
Ethics statement The animal study was approved by Animal Experimentation Ethics Committee at the Chinese University of Hong Kong. The study was conducted in accordance with the local legislation and institutional requirements. Author contributions Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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