High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons

Abstract

High-mobility group box 1 (HMGB1), a multifunctional nuclear protein, exists mainly within the nucleus of all mammal eukaryotic cells. It is actively secreted by the necrotic cells as a response to the inflammatory signaling pathway. HMGB1 binds to receptor ligands as RAGE, and TLR and becomes a pro-inflammatory cytokine with a robust capacity to trigger inflammatory response. It is a critical mediator of the pathogenesis of systemic inflammation in numerous inflammatory disorders. Release of HMGB1 is associated with different viral infections and strongly participates in the regulation of viral replication cycles. In COVID-19 era, high HMGB1 serum levels were observed in COVID-19 patients and linked with the disease severity, development of cytokine storm (CS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). SARS-CoV-2-induced cytolytic effect may encourage release of HMGB1 due to nuclear damage. Besides, HMGB1 activates release of pro-inflammatory cytokines from immune cells and up-regulation of angiotensin I-converting enzyme 2 (ACE2). Therefore, targeting of the HMGB1 pathway by anti-HMGB1 agents, such as heparin, resveratrol and metformin, may decrease COVID-19 severity. HMGB1 signaling pathway has noteworthy role in the pathogenesis of SARS-CoV-2 infections and linked with development of ALI and ARDS in COVID-19 patients. Different endogenous and exogenous agents may affect release and activation of HMGB1 pathway. Targeting of HMGB1-mediated TLR2/TLR4, RAGE and MAPK signaling, might be a new promising drug candidate against development of ALI and/or ARDS in severely affected COVID-19 patients.

Keywords: Acute respiratory distress syndrome; Anti-HMGB1 agents; COVID-19; High-mobility group box 1; SARS-CoV-2.

Fig. 1

Role of HMGB1 in the development of acute lung injury (ALI): extracellular high-mobility group box 1 (HMGB1) activates cell membrane TLR2, TLR4 and RAGE receptors. Activation of RAGE receptors leads to triggering of ROS-dependent activation of MAPK pathway. Though, activations of TLR2 and TLR4 by HMGB1 trigger activations of intracellular myeloid differentiation 88 (MyD88), which activates inhibitor of nuclear factor kappa B kinase (IKK-β). Both of IKK-β and mitogen-activated protein kinase (MAPK) stimulate NF-κB signaling pathway. However, extracellular HMGB1 may directly activate NF-κB through phosphatidyl-inositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) independent of TLRs or RAGE receptors leading to release of pro-inflammatory cytokines that result in ALI

Fig. 2

SARS-CoV-2-induced ALI/ARDS: SARS-CoV-2 infection leads to activation release of extracellular high-mobility group box 1 (HMGB1) through down-regulation of ACE2, and activation of NLRP3 inflammasome, autophagy and TLR2/TLR4. HMGB1 activates TLR2, TLR4, RAGE receptors and mitogen-activated protein kinase (MAPK), provoke activation of NF-κB signaling pathway, which induces NETs formation, thrombosis and cytokine storm. These inflammatory mediators cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)