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

Front Immunol. 2023 Nov 3:14:1264447. doi: 10.3389/fimmu.2023.1264447. eCollection 2023.

Abstract

"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-α, and MCP-1 via a Mincle-Syk/NF-κB-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-κB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-α, 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 suppressing Mincle-Syk/NF-κB signaling in vivo and in vitro. In conclusion, SARS-CoV-2 N protein-induced AKI in db/db mice is associated with Mincle-dependent M1 macrophage activation. Inhibition of this pathway may be a mechanism through which quercetin inhibits COVID-19-associated AKI.

Keywords: AKI; M1 macrophage; Mincle; N protein; SARS-CoV-2; quercetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury* / metabolism
  • Animals
  • COVID-19* / metabolism
  • Diabetes Mellitus* / metabolism
  • HMGB1 Protein* / metabolism
  • Humans
  • Interleukin-6 / metabolism
  • Macrophage Activation
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Quercetin / pharmacology
  • SARS-CoV-2 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • NF-kappa B
  • HMGB1 Protein
  • Quercetin
  • Tumor Necrosis Factor-alpha
  • Interleukin-6

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by grants from the Research Grants Council of Hong Kong (GRF 14104019, 14101121, and R4012-18); the High-Level Hospital Construction Project from Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science(KJ012019108), the Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology Department (2019B121205005), the Sichuan Science and Technology Program (2022YFH0118), and Health and Medical Research Fund of Hong Kong (HMRF 06173986), and the Lui Che Woo Institute of Innovative Medicine (CARE program).