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.
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References
Ahmadian, Khatibi, Soofiyani, Abediazar, Shoja et al., Covid-19 and kidney injury: Pathophysiology and molecular mechanisms, Rev Med Virol,
doi:10.1002/rmv.2176Bernini, Velotti, Natural polyphenols as immunomodulators to rescue immune response homeostasis: quercetin as a research model against severe COVID-19, Molecules,
doi:10.3390/molecules26195803Chan, Chaudhary, Saha, Chauhan, Vaid et al., AKI in hospitalized patients with COVID-19, J Am Soc Nephrol,
doi:10.1681/ASN.2020050615Cheng, Luo, Wang, Zhang, Wang et al., Kidney disease is associated with in-hospital death of patients with COVID-19, Kidney Int,
doi:10.1016/j.kint.2020.03.005Cummings, Baldwin, Abrams, Jacobson, Meyer et al., Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)31189-2Diao, Wang, Wang, Feng, Zhang et al., Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection, Nat Commun,
doi:10.1038/s41467-021-22781-1Diniz, Souza, Duarte, Sousa, Mechanistic aspects and therapeutic potential of quercetin against COVID-19-associated acute kidney injury, Molecules,
doi:10.3390/molecules25235772Fukao, Nagasawa, Nihei, Hiki, Naito et al., COVID-19-induced acute renal tubular injury associated with elevation of serum inflammatory cytokine, Clin Exp Nephrol,
doi:10.1007/s10157-021-02101-zGabarre, Dumas, Dupont, Darmon, Azoulay et al., Acute kidney injury in critically ill patients with COVID-19, Intensive Care Med,
doi:10.1007/s00134-020-06153-9Gao, Ding, Dong, Zhang, Azkur et al., Risk factors for severe and critically ill COVID-19 patients: A review, Allergy,
doi:10.1111/all.14657Gradin, Andersson, Luther, Anderberg, Rubertsson et al., Urinary cytokines correlate with acute kidney injury in critically ill COVID-19 patients, Cytokine,
doi:10.1016/j.cyto.2021.155589Gu, Zhang, Cen, Wu, Lu et al., Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study, PloS One,
doi:10.1371/journal.pone.0245209Gupta, Coca, Chan, Melamed, Brenner et al., AKI treated with renal replacement therapy in critically ill patients with COVID-19, J Am Soc Nephrol,
doi:10.1681/ASN.2020060897Izzedine, Jhaveri, Acute kidney injury in patients with COVID-19: an update on the pathophysiology, Nephrol Dial Transplant,
doi:10.1093/ndt/gfaa184Jiang, Chen, Shao, Lu, Zhou, HMGB1 silencing in macrophages prevented their functional skewing and ameliorated EAM development: Nuclear HMGB1 may be a checkpoint molecule of macrophage reprogramming, Int Immunopharmacol,
doi:10.1016/j.intimp.2018.01.013Kingeter, Lin, C-type lectin receptor-induced NF-kB activation in innate immune and inflammatory responses, Cell Mol Immunol,
doi:10.1038/cmi.2011.58Lan, Mu, Nikolic-Paterson, Atkins, A novel, simple, reliable, and sensitive method for multiple immunoenzyme staining: use of microwave oven heating to block antibody crossreactivity and retrieve antigens, J Histochem Cytochem,
doi:10.1177/43.1.7822770Legrand, Bell, Forni, Joannidis, Koyner et al., Pathophysiology of COVID-19-associated acute kidney injury, Nat Rev Nephrol,
doi:10.1038/s41581-021-00452-0Li, Gong, Zhong, Wang, Guo et al., Neutralization of the extracellular HMGB1 released by ischaemic damaged renal cells protects against renal ischaemia-reperfusion injury, Nephrol Dial Transplant,
doi:10.1093/ndt/gfq466Li, Liu, Meng, Yin, Gao et al., Critical roles of cytokine storm and secondary bacterial infection in acute kidney injury development in COVID-19: A multi-center retrospective cohort study, J Med Virol,
doi:10.1002/jmv.27234Liang, Chen, Wu, Huang, Wei, SARS-CoV-2 N protein induces acute kidney injury in diabetic mice via the Smad3-Ripk3/MLKL necroptosis pathway, Signal Transduct Target Ther,
doi:10.1038/s41392-023-01410-xLiu, Li, Liu, Liang, Wang et al., Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients, EBioMedicine,
doi:10.1016/j.ebiom.2020.102763Lu, Wu, Liu, Ruan, Zhang et al., Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2 macrophage polarization, Biochem Pharmacol,
doi:10.1016/j.bcp.2018.05.007Lv, Tang, Li, You, Li et al., The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation, Kidney Int,
doi:10.1016/j.kint.2016.10.020Munafo, Donati, Brindani, Ottonello, Armirotti et al., Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase, Sci Rep,
doi:10.1038/s41598-022-14664-2Pan, Shen, Yu, Ge, Chen et al., SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation, Nat Commun,
doi:10.1038/s41467-021-25015-6Parthasarathy, Martinelli, Vollmann, Best, Therien, The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders, Biochem Pharmacol,
doi:10.1016/j.bcp.2021.114847Pierro, Derosa, Maffioli, Bertuccioli, Togni et al., Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: A prospective, randomized, controlled, and open-label study, Int J Gen Med,
doi:10.2147/IJGM.S318720Pierro, Iqtadar, Khan, Mumtaz, Chaudhry et al., Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial, Int J Gen Med,
doi:10.2147/IJGM.S318949Tan, Wang, Deng, Zhong, Yan et al., Quercetin protects against cisplatin-induced acute kidney injury by inhibiting Mincle/Syk/NF-kB signaling maintained macrophage inflammation, Phytother Res,
doi:10.1002/ptr.6507Tian, Zhang, Tang, Guo, Dong et al., HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury, Am J Physiol Renal Physiol,
doi:10.1152/ajprenal.00484.2014Wang, Chen, Hu, Pan, Liang et al., SARS-coV-2 N protein induces acute kidney injury via smad3-dependent G1 cell cycle arrest mechanism, Adv Sci (Weinh),
doi:10.1002/advs.202103248Wang, Yang, Li, Huang, Jiang et al., Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction, Virol J,
doi:10.1186/s12985-021-01588-yWu, Ma, Cai, Zhuang, Zhao, RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-kB hyper-activation and inflammation, Signal Transduct Target Ther,
doi:10.1038/s41392-021-00575-7Wu, Ma, Wang, Corpuz, Panchapakesan et al., HMGB1 contributes to kidney ischemia reperfusion injury, J Am Soc Nephrol,
doi:10.1681/ASN.2009101048Wu, Wang, Liang, Chen, Wei et al., Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest, Mol Ther,
doi:10.1016/j.ymthe.2022.12.002Yanai, Ban, Taniguchi, High-mobility group box family of proteins: ligand and sensor for innate immunity, Trends Immunol,
doi:10.1016/j.it.2012.10.005Yang, Xie, Tu, Fu, Xu et al., The signal pathways and treatment of cytokine storm in COVID-19, Signal Transduct Target Ther,
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'abstract': '<jats:p>“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 <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-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 <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-κB 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>',
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'crossreactivity and retrieve antigens',
'volume': '43',
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'the M1 macrophage phenotype in acute renal inflammation',
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'hyperinflammation',
'volume': '12',
'author': 'Pan',
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