{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:24:15Z","timestamp":1788535455248,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T00:00:00Z","timestamp":1698969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\u201cCytokine storm\u201d 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-\u03b1, and MCP-1 via a Mincle-Syk\/NF-\u03baB-dependent mechanism. This was further confirmed <jats:italic>in vitro<\/jats:italic> 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-\u03baB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-\u03b1, and MCP-1 <jats:italic>in vitro<\/jats:italic>. 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-\u03baB signaling <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. 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.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1264447","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T09:49:45Z","timestamp":1699004985000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["SARS-CoV-2 N protein induced acute kidney injury in diabetic db\/db mice is associated with a Mincle-dependent M1 macrophage 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