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. 2020 Dec 7;6(12):e05672.
doi: 10.1016/j.heliyon.2020.e05672. eCollection 2020 Dec.

HMGB1 as a potential biomarker and therapeutic target for severe COVID-19

Ruochan Chen  1   2 , Yan Huang  1   2 , Jun Quan  1   2 , Jiao Liu  3 , Haichao Wang  4 , Timothy R Billiar  5 , Michael T Lotze  5 , Herbert J Zeh  6 , Rui Kang  6 , Daolin Tang  6
Affiliations

HMGB1 as a potential biomarker and therapeutic target for severe COVID-19

Ruochan Chen et al. Heliyon. .

Abstract

COVID-19 has attracted global attention due to its rapid spread around the world with substantial morbidity and associated mortality. Severe COVID-19 can be complicated by the acute respiratory distress syndrome, sepsis and septic shock leading to death. These complications are thought to result from an overactivation of the immune system, leading to a cytokine storm syndrome associated with multiple organ failure. Here, we report that high mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP) and a central mediator of lethal inflammation, could be a potential target for innovative therapeutic strategies for COVID-19. Serum HMGB1 in severe COVID-19 patients is elevated (189.40 ± 140.88 ng/ml). Exogenous HMGB1 induces the expression of SARS-CoV-2 entry receptor ACE2 in alveolar epithelial cells in an AGER-dependent manner. Importantly, genetic (using AGER siRNA) or pharmacological (using glycyrrhizin, chloroquine, hydroxychloroquine, and FPS-ZM1) inhibition of the HMGB1-AGER pathway blocks ACE2 expression. Thus, HMGB1 inhibitors are likewise promising drug candidates for the treatment of patients suffering from COVID-19.

Keywords: COVID-19; Cell culture; Cell death; HMGB1; Immunology; Infectious disease; Inflammation; Microbiology; Virology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Enhanced HMGB1 blood levels in COVID-19 patients. ELISA analysis of the serum HMGB1 level in severe COVID-19 patients, non-severe COVID-19 patients, and healthy controls (t test).
Figure 2
Figure 2
Recombinant human HMGB1 induces ACE2 expression. Q-PCR analysis of ACE2 mRNA in indicated Calu-3 (A), HepG2 (B), Caco2 (C) and RT4 (D) cells following treatment with human HMGB1 protein (200 ng/ml) or low-dose LPS (1 ng/ml) for 3–24 h (n = 3, ANOVA test). Data represent the mean ± SD of three independent experiments, each performed in triplicate, and are presented relative to control.
Figure 3
Figure 3
AGER is required for HMGB1-induced ACE2 expression in lung epithelial cells. (A) ELISA analysis of TNF release in indicated human monocytes (THP1) following treatment with human HMGB1 protein (200 ng/ml) for 24 h (n = 3, t test). (B) Western blot analysis of protein expression in human lung epithelial cells (Calu-3) after siRNA-mediated depletion of TLR4 or AGER. (C) Q-PCR analysis of ACE2 mRNA in indicated Calu-3 cells following treatment with human HMGB1 protein (200 ng/ml) for 24 h (n = 3, t test). Data represent the mean ± SD of three independent experiments, each performed in triplicate, and are presented relative to control.
Figure 4
Figure 4
Pharmacological inhibition of HMGB1-AGER signaling limits ACE2 expression. (A, B) Q-PCR analysis of ACE2 mRNA in indicated Calu-3 cells following treatment with human HMGB1 protein (200 ng/ml) in the absence or presence of glycyrrhizin (Gly), chloroquine (CQ), hydroxychloroquine (HCQ), and AGER inhibitor FPS-ZM1 for 12 or 24 h (n = 3, ∗P < 0.05 versus HMGB1 group, ANOVA test). (C) Schematic depiction of the role of HMGB1 release in COVID-19. HMGB1 may be involved in COVID-19 through at least two mechanisms: one is TLR4-mediated cytokine storm in immune cells (e.g., macrophages and monocytes), and the other is AGER-mediated ACE2 expression in alveolar epithelial cells. Data represent the mean ± SD of three independent experiments, each performed in triplicate, and are presented relative to control.
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