Extracellular HMGB1 protein is known to induce inflammatory responses leading to an inflammatory storm. The outbreak of the Severe Acute Respiratory Syndrome COVID-19 due to the SARS-CoV-2 virus has resulted in a huge health concern worldwide. Recent data revealed that plasma/serum HMGB1 levels of patients suffering from inflammation-mediated disorders-such as COVID-19, cancer, and autoimmune disorders-correlate positively with disease severity and vice versa. A late release of HMGB1 in sepsis suggests the existence of a wide therapeutic window for treating sepsis. Rapid and accurate methods for the detection of HMGB1 levels in plasma/serum are, therefore, of great importance for monitoring the occurrence, treatment success, and survival prediction of patients with inflammation-mediated diseases. In this review, we briefly explain the role of HMGB1 in the cell, and particularly the involvement of extracellular HMGB1 (released from the cells) in inflammation-mediated diseases, with an emphasis on COVID-19. The current assays to measure HMGB1 levels in human plasma-Western blotting, ELISA, EMSA, and a new approach based on electrochemical immunosensors, including some of our preliminary results-are presented and thoroughly discussed.

Department of Biochemistry Faculty of Science Masaryk University 60177 Brno Czech Republic

Institute of Biophysics of the Czech Academy of Sciences 61200 Brno Czech Republic

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Stros M. HMGB proteins: Interactions with DNA and chromatin. Biochim. Biophys. Acta. 2010;1799:101–113. doi: 10.1016/j.bbagrm.2009.09.008. PubMed DOI

Agresti A., Bianchi M.E. HMGB proteins and gene expression. Curr. Opin. Genet. Dev. 2003;13:170–178. doi: 10.1016/S0959-437X(03)00023-6. PubMed DOI

Calogero S., Grassi F., Aguzzi A., Voigtlander T., Ferrier P., Ferrari S., Bianchi M.E. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat. Genet. 1999;22:276–280. doi: 10.1038/10338. PubMed DOI

Stros M., Ozaki T., Bacikova A., Kageyama H., Nakagawara A. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J. Biol. Chem. 2002;277:7157–7164. doi: 10.1074/jbc.M110233200. PubMed DOI

Kang R., Zhang Q., Zeh H.J., 3rd, Lotze M.T., Tang D. HMGB1 in cancer: Good, bad, or both? Clin. Cancer Res. 2013;19:4046–4057. doi: 10.1158/1078-0432.CCR-13-0495. PubMed DOI PMC

Mandke P., Vasquez K.M. Interactions of high mobility group box protein 1 (HMGB1) with nucleic acids: Implications in DNA repair and immune responses. DNA Repair. 2019;83:102701. doi: 10.1016/j.dnarep.2019.102701. PubMed DOI PMC

Bonaldi T., Talamo F., Scaffidi P., Ferrera D., Porto A., Bachi A., Rubartelli A., Agresti A., Bianchi M.E. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003;22:5551–5560. doi: 10.1093/emboj/cdg516. PubMed DOI PMC

Venereau E., Casalgrandi M., Schiraldi M., Antoine D.J., Cattaneo A., De Marchis F., Liu J., Antonelli A., Preti A., Raeli L., et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 2012;209:1519–1528. doi: 10.1084/jem.20120189. PubMed DOI PMC

Kang R., Livesey K.M., Zeh H.J., Loze M.T., Tang D. HMGB1: A novel Beclin 1-binding protein active in autophagy. Autophagy. 2010;6:1209–1211. doi: 10.4161/auto.6.8.13651. PubMed DOI

Lotze M.T., Tracey K.J. High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 2005;5:331–342. doi: 10.1038/nri1594. PubMed DOI

Kapurniotu A., Gokce O., Bernhagen J. The multitasking potential of alarmins and atypical chemokines. Front. Med. 2019;6:3. doi: 10.3389/fmed.2019.00003. PubMed DOI PMC

Kang R., Chen R., Zhang Q., Hou W., Wu S., Cao L., Huang J., Yu Y., Fan X.G., Yan Z., et al. HMGB1 in health and disease. Mol. Asp. Med. 2014;40:1–116. doi: 10.1016/j.mam.2014.05.001. PubMed DOI PMC

Yang H., Wang H., Andersson U. Targeting inflammation driven by HMGB1. Front. Immunol. 2020;11:484. doi: 10.3389/fimmu.2020.00484. PubMed DOI PMC

Wyganowska-Swiatkowska M., Nohawica M., Grocholewicz K., Nowak G. Influence of herbal medicines on HMGB1 release, SARS-CoV-2 viral attachment, acute respiratory failure, and sepsis. A literature review. Int. J. Mol. Sci. 2020;21:4639. doi: 10.3390/ijms21134639. PubMed DOI PMC

Zhu B., Zhu Q., Li N., Wu T., Liu S., Liu S. Association of serum/plasma high mobility group box 1 with autoimmune diseases: A systematic review and meta-analysis. Medicine. 2018;97:e11531. doi: 10.1097/MD.0000000000011531. PubMed DOI PMC

Xue J., Suarez J.S., Minaai M., Li S., Gaudino G., Pass H.I., Carbone M., Yang H. HMGB1 as a therapeutic target in disease. J. Cell. Physiol. 2021;236:3406–3419. doi: 10.1002/jcp.30125. PubMed DOI PMC

Andersson U., Yang H., Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin. Ther. Targets. 2018;22:263–277. doi: 10.1080/14728222.2018.1439924. PubMed DOI

Cai X., Ding H., Liu Y., Pan G., Li Q., Yang Z., Liu W. Expression of HMGB2 indicates worse survival of patients and is required for the maintenance of Warburg effect in pancreatic cancer. Acta Biochim. Biophys. Sin. 2017;49:119–127. doi: 10.1093/abbs/gmw124. PubMed DOI

Wu T., Zhang W., Yang G., Li H., Chen Q., Song R., Zhao L. HMGB1 overexpression as a prognostic factor for survival in cancer: A meta-analysis and systematic review. Oncotarget. 2016;7:50417–50427. doi: 10.18632/oncotarget.10413. PubMed DOI PMC

Gorgulho C.M., Romagnoli G.G., Bharthi R., Lotze M.T. Johnny on the spot-chronic inflammation is driven by HMGB1. Front. Immunol. 2019;10:1561. doi: 10.3389/fimmu.2019.01561. PubMed DOI PMC

Lin T., Zhang Y., Lin Z., Peng L. Roles of HMGBs in Prognosis and Immunotherapy: A Pan-Cancer Analysis. Front. Genet. 2021;12:764245. doi: 10.3389/fgene.2021.764245. PubMed DOI PMC

Hu B., Guo H., Zhou P., Shi Z.L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 2021;19:141–154. doi: 10.1038/s41579-020-00459-7. PubMed DOI PMC

Zhou P., Yang X.L., Wang X.G., Hu B., Zhang L., Zhang W., Si H.R., Zhu Y., Li B., Huang C.L., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi: 10.1038/s41586-020-2012-7. PubMed DOI PMC

Andersson U., Ottestad W., Tracey K.J. Extracellular HMGB1: A therapeutic target in severe pulmonary inflammation including COVID-19? Mol. Med. 2020;26:42. doi: 10.1186/s10020-020-00172-4. PubMed DOI PMC

Andersson U., Yang H., Harris H. High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells. Semin. Immunol. 2018;38:40–48. doi: 10.1016/j.smim.2018.02.011. PubMed DOI

Chen L., Long X., Xu Q., Tan J., Wang G., Cao Y., Wei J., Luo H., Zhu H., Huang L., et al. Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients. Cell. Mol. Immunol. 2020;17:992–994. doi: 10.1038/s41423-020-0492-x. PubMed DOI PMC

Wei J., Alfajaro M.M., Hanna R.E., DeWeirdt P.C., Strine M.S., Lu-Culligan W.J., Zhang S.M., Graziano V.R., Schmitz C.O., Chen J.S., et al. Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection. bioRxiv. 2020 doi: 10.1101/2020.06.16.155101. PubMed DOI

Chen R., Huang Y., Quan J., Liu J., Wang H., Billiar T.R., Lotze M.T., Zeh H.J., Kang R., Tang D. HMGB1 as a potential biomarker and therapeutic target for severe COVID-19. Heliyon. 2020;6:e05672. doi: 10.1016/j.heliyon.2020.e05672. PubMed DOI PMC

Qi Y.F., Zhang J., Wang L., Shenoy V., Krause E., Oh S.P., Pepine C.J., Katovich M.J., Raizada M.K. Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia. J. Mol. Med. 2016;94:37–49. doi: 10.1007/s00109-015-1356-1. PubMed DOI PMC

Street M.E. HMGB1: A possible crucial therapeutic target for COVID-19? Horm. Res. Paediatr. 2020;93:73–75. doi: 10.1159/000508291. PubMed DOI PMC

Sivakorn C., Dechsanga J., Jamjumrus L., Boonnak K., Schultz M.J., Dorndorp A.M., Phumratanaprapin W., Ratanarat R., Naorungroj T., Wattanawinitchai P., et al. High mobility group box 1 and interleukin 6 at intensive care unit admission as biomarkers in critically ill COVID-19 patients. Am. J. Trop. Med. Hyg. 2021;105:73–80. doi: 10.4269/ajtmh.21-0165. PubMed DOI PMC

Di Salvo E., Di Gioacchino M., Tonacci A., Casciaro M., Gangemi S. Alarmins, COVID-19 and comorbidities. Ann. Med. 2021;53:777–785. doi: 10.1080/07853890.2021.1921252. PubMed DOI PMC

Weng L., Guo L., Vachani A., Mesaros C., Blair I.A. Quantification of serum high mobility group box 1 by liquid chromatography/high-resolution mass spectrometry: Implications for its role in immunity, inflammation, and cancer. Anal. Chem. 2018;90:7552–7560. doi: 10.1021/acs.analchem.8b01175. PubMed DOI PMC

Urbonaviciute V., Furnrohr B.G., Weber C., Haslbeck M., Wilhelm S., Herrmann M., Voll R.E. Factors masking HMGB1 in human serum and plasma. J. Leukoc. Biol. 2007;81:67–74. doi: 10.1189/jlb.0306196. PubMed DOI

Abdulahad D.A., Westra J., Limburg P.C., Kallenberg C.G., Bijl M. HMGB1 in systemic lupus erythematosus: Its role in cutaneous lesions development. Autoimmun. Rev. 2010;9:661–665. doi: 10.1016/j.autrev.2010.05.015. PubMed DOI

Barnay-Verdier S., Gaillard C., Messmer M., Borde C., Gibot S., Marechal V. PCA-ELISA: A sensitive method to quantify free and masked forms of HMGB1. Cytokine. 2011;55:4–7. doi: 10.1016/j.cyto.2011.03.011. PubMed DOI

Wang H., Zhao L., Li J., Zhu S., Yeung M. Analysis of the released nuclear cytokine HMGB1 in human serum. Methods Mol. Biol. 2014;1172:13–25. doi: 10.1007/978-1-4939-0928-5_2. PubMed DOI

Gaillard C., Strauss F. High affinity binding of proteins HMG1 and HMG2 to semicatenated DNA loops. BMC Mol. Biol. 2000;1:1. doi: 10.1186/1471-2199-1-1. PubMed DOI PMC

Gaillard C., Borde C., Gozlan J., Marechal V., Strauss F. A high-sensitivity method for detection and measurement of HMGB1 protein concentration by high-affinity binding to DNA hemicatenanes. PLoS ONE. 2008;3:e2855. doi: 10.1371/journal.pone.0002855. PubMed DOI PMC

Stros M., Muselikova-Polanska E., Pospisilova S., Strauss F. High-affinity binding of tumor-suppressor protein p53 and HMGB1 to hemicatenated DNA loops. Biochemistry. 2004;43:7215–7225. doi: 10.1021/bi049928k. PubMed DOI

Jaouen S., de Koning L., Gaillard C., Muselikova-Polanska E., Stros M., Strauss F. Determinants of specific binding of HMGB1 protein to hemicatenated DNA loops. J. Mol. Biol. 2005;353:822–837. doi: 10.1016/j.jmb.2005.08.073. PubMed DOI

Polanska E., Pospisilova S., Stros M. Binding of histone H1 to DNA is differentially modulated by redox state of HMGB1. PLoS ONE. 2014;9:e89070. doi: 10.1371/journal.pone.0089070. PubMed DOI PMC

Stros M., Polanska E., Kucirek M., Pospisilova S. Histone H1 differentially inhibits DNA bending by reduced and oxidized HMGB1 protein. PLoS ONE. 2015;10:e0138774. doi: 10.1371/journal.pone.0138774. PubMed DOI PMC

Fanjul-Bolado P., Gonzalez-Garcia M.B., Costa-Garcia A. Amperometric detection in TMB/HRP-based assays. Anal. Bioanal. Chem. 2005;382:297–302. doi: 10.1007/s00216-005-3084-9. PubMed DOI

Skládal P. Advances in electrochemical immunosensors for pathogens. Curr. Opin. Electrochem. 2019;14:66–70. doi: 10.1016/j.coelec.2018.12.010. DOI

Lacina K., Sopoušek J., Čunderlová V., Hlaváček A., Václavek T., Lacinová V. Biosensing based on electrochemical impedance spectroscopy: Influence of the often-ignored molecular charge. Electrochem. Commun. 2018;93:183–186. doi: 10.1016/j.elecom.2018.07.015. DOI

Cao S., Yuan R., Chai Y., Zhang L., Li X., Gao F. A mediator-free amperometric hydrogen peroxide biosensor based on HRP immobilized on a nano-Au/poly 2,6-pyridinediamine-coated electrode. Bioprocess Biosyst. Eng. 2007;30:71–78. doi: 10.1007/s00449-006-0100-1. PubMed DOI

Pastucha M., Farka Z., Lacina K., Mikusova Z., Skladal P. Magnetic nanoparticles for smart electrochemical immunoassays: A review on recent developments. Mikrochim. Acta. 2019;186:312. doi: 10.1007/s00604-019-3410-0. PubMed DOI

Farka Z., Cunderlova V., Horackova V., Pastucha M., Mikusova Z., Hlavacek A., Skladal P. Prussian blue nanoparticles as a catalytic label in a sandwich nanozyme-linked immunosorbent assay. Anal. Chem. 2018;90:2348–2354. doi: 10.1021/acs.analchem.7b04883. PubMed DOI

Venereau E., De Leo F., Mezzapelle R., Careccia G., Musco G., Bianchi M.E. HMGB1 as biomarker and drug target. Pharmacol. Res. 2016;111:534–544. doi: 10.1016/j.phrs.2016.06.031. PubMed DOI

HMGB-1 as a predictor of major bleeding requiring activation of a massive transfusion protocol in severe trauma