SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation
“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 patt...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1264447/full |
| _version_ | 1797639926709223424 |
|---|---|
| author | Wenjing Wu Wenjing Wu Wenjing Wu Wenjing Wu Wenjing Wu Wenbiao Wang Wenbiao Wang Liying Liang Liying Liang Junzhe Chen Junzhe Chen Sifan Sun Sifan Sun Biao Wei Yu Zhong Xiao-Ru Huang Xiao-Ru Huang Xiao-Ru Huang Jian Liu Xiaoqin Wang Xiaoqin Wang Xueqing Yu Hui-Yao Lan Hui-Yao Lan |
| author_facet | Wenjing Wu Wenjing Wu Wenjing Wu Wenjing Wu Wenjing Wu Wenbiao Wang Wenbiao Wang Liying Liang Liying Liang Junzhe Chen Junzhe Chen Sifan Sun Sifan Sun Biao Wei Yu Zhong Xiao-Ru Huang Xiao-Ru Huang Xiao-Ru Huang Jian Liu Xiaoqin Wang Xiaoqin Wang Xueqing Yu Hui-Yao Lan Hui-Yao Lan |
| author_sort | Wenjing Wu |
| collection | DOAJ |
| description | “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. |
| first_indexed | 2024-03-11T13:24:31Z |
| format | Article |
| id | doaj.art-6b5b8846401a4f6ba697725cf8be026e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T13:24:31Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-6b5b8846401a4f6ba697725cf8be026e2023-11-03T09:49:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12644471264447SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activationWenjing Wu0Wenjing Wu1Wenjing Wu2Wenjing Wu3Wenjing Wu4Wenbiao Wang5Wenbiao Wang6Liying Liang7Liying Liang8Junzhe Chen9Junzhe Chen10Sifan Sun11Sifan Sun12Biao Wei13Yu Zhong14Xiao-Ru Huang15Xiao-Ru Huang16Xiao-Ru Huang17Jian Liu18Xiaoqin Wang19Xiaoqin Wang20Xueqing Yu21Hui-Yao Lan22Hui-Yao Lan23Guangdong Cardiovascular Institute, Guangzhou, ChinaGuangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Departments of Nephrology and Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaThe First Clinical College, Hubei University of Chinese Medicine, Wuhan, ChinaDepartment of Nephrology, Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, ChinaGuangdong Cardiovascular Institute, Guangzhou, ChinaGuangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Departments of Nephrology and Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaGuangdong Cardiovascular Institute, Guangzhou, ChinaGuangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Departments of Nephrology and Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, ChinaThe First Clinical College, Hubei University of Chinese Medicine, Wuhan, ChinaDepartment of Nephrology, Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, ChinaGuangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Departments of Nephrology and Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, ChinaGuangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Departments of Nephrology and Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, ChinaDepartments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China“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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1264447/fullSARS-CoV-2N proteinAKIquercetinMincleM1 macrophage |
| spellingShingle | Wenjing Wu Wenjing Wu Wenjing Wu Wenjing Wu Wenjing Wu Wenbiao Wang Wenbiao Wang Liying Liang Liying Liang Junzhe Chen Junzhe Chen Sifan Sun Sifan Sun Biao Wei Yu Zhong Xiao-Ru Huang Xiao-Ru Huang Xiao-Ru Huang Jian Liu Xiaoqin Wang Xiaoqin Wang Xueqing Yu Hui-Yao Lan Hui-Yao Lan SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation Frontiers in Immunology SARS-CoV-2 N protein AKI quercetin Mincle M1 macrophage |
| title | SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation |
| title_full | SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation |
| title_fullStr | SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation |
| title_full_unstemmed | SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation |
| title_short | SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation |
| title_sort | sars cov 2 n protein induced acute kidney injury in diabetic db db mice is associated with a mincle dependent m1 macrophage activation |
| topic | SARS-CoV-2 N protein AKI quercetin Mincle M1 macrophage |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1264447/full |
| work_keys_str_mv | AT wenjingwu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT wenjingwu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT wenjingwu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT wenjingwu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT wenjingwu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT wenbiaowang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT wenbiaowang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT liyingliang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT liyingliang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT junzhechen sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT junzhechen sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT sifansun sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT sifansun sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT biaowei sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT yuzhong sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT xiaoruhuang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT xiaoruhuang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT xiaoruhuang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT jianliu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT xiaoqinwang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT xiaoqinwang sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT xueqingyu sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT huiyaolan sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation AT huiyaolan sarscov2nproteininducedacutekidneyinjuryindiabeticdbdbmiceisassociatedwithamincledependentm1macrophageactivation |