The role of extracellular histones in COVID‐19

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) had spread from China and, within 2 months, became a global pandemic. The infection from this disease can cause a diversity of symptoms ranging from asymptomatic to severe acute respiratory distress syndrome with an increased risk of vascular hyperpermeability, pulmonary inflammation, extensive lung damage, and thrombosis. One of the host defense systems against coronavirus disease 2019 (COVID‐19) is the formation of neutrophil extracellular traps (NETs). Numerous studies on this disease have revealed the presence of elevated levels of NET components, such as cell‐free DNA, extracellular histones, neutrophil elastase, and myeloperoxidase, in plasma, serum, and tracheal aspirates of severe COVID‐19 patients. Extracellular histones, a major component of NETs, are clinically very relevant as they represent promising biomarkers and drug targets, given that several studies have identified histones as key mediators in the onset and progression of various diseases, including COVID‐19. However, the role of extracellular histones in COVID‐19 per se remains relatively underexplored. Histones are nuclear proteins that can be released into the extracellular space via apoptosis, necrosis, or NET formation and are then regarded as cytotoxic damage‐associated molecular patterns that have the potential to damage tissues and impair organ function. This review will highlight the mechanisms of extracellular histone‐mediated cytotoxicity and focus on the role that histones play in COVID‐19. Thereby, this paper facilitates a bench‐to‐bedside view of extracellular histone‐mediated cytotoxicity, its role in COVID‐19, and histones as potential drug targets and biomarkers for future theranostics in the clinical treatment of COVID‐19 patients.

Targeting circulating high mobility group box-1 and histones by extracorporeal blood purification as an immunomodulation strategy against critical illnesses

“…Beyond HMGB1, histones are another group of basic nucleoproteins mainly derived from neutrophil extracellular traps that contribute to a dysregulated inflammatory response, activation of the coagulation system and organ dysfunction in sepsis [ 12 ], liver failure [ 13 , 26 ], trauma [ 16 , 46 ], SAP [ 14 , 47 ], acute respiratory distress syndrome (ARDS) [ 48 , 49 ] and COVID-19 [ 18 ]. Circulating histones, also known as extracellular histones, significantly activate TLR-dependent and NLPR3 inflammasome pathways to trigger the host innate immune response, resulting in the activation of the NF-κB pathway and subsequent release of proinflammatory cytokines such as TNF-α, IL-6, IL-1β and IL-18 [ 12 , 50 , 51 ].…”

“…Currently, an increasing number of endogenous host-derived molecules, including S100 proteins, heat shock proteins, high mobility group box 1 protein (HMGB1), circulating histones and glycans such as heparan sulfate, are considered DAMPs [ 10 ]. Among them, HMGB1 and histones are abundantly studied because they significantly mediate lethal systemic inflammation, complement and coagulation activation, endothelial injury and organ dysfunction in various critical illnesses, such as sepsis [ 11 , 12 ], acute liver failure [ 13 ], pancreatitis [ 14 , 15 ], multiple trauma [ 16 ] and severe COVID-19 [ 17 , 18 ]. Accumulating evidence collectively suggests that high levels of serum HMGB1 and histones significantly correlate with disease severity and mortality in critically ill patients [ 16 , 19 – 23 ].…”

Monocytic HLA-DR Expression in Immune Responses of Acute Pancreatitis and COVID-19

“…Cytokines and damage-associated molecular patterns (DAMPs), such as histones, high-mobility group box-1 protein, hyaluronan fragments, mitochondrial DNA, and heat-shock proteins are released from dying or injured cells in the injured pancreas or SARS-CoV-2 infected tissues—particularly lungs. This is associated with and results from a series of molecular events, including premature trypsinogen activation, calcium overload, mitochondria failure, endoplasmic reticulum stress, impaired autophagy, or by SARS-CoV-2 proliferation and release, respectively [ 6 , 30 , 31 , 32 , 33 ]. Interaction of DAMPs with pattern-recognition receptors (PRRs), including Toll-like receptors and NLRP3 inflammasome of the adjacent parenchymal cells or immune cells, promotes the production of various pro-inflammatory cytokines and chemokines [ 31 , 34 , 35 , 36 ].…”

“…This is associated with and results from a series of molecular events, including premature trypsinogen activation, calcium overload, mitochondria failure, endoplasmic reticulum stress, impaired autophagy, or by SARS-CoV-2 proliferation and release, respectively [ 6 , 30 , 31 , 32 , 33 ]. Interaction of DAMPs with pattern-recognition receptors (PRRs), including Toll-like receptors and NLRP3 inflammasome of the adjacent parenchymal cells or immune cells, promotes the production of various pro-inflammatory cytokines and chemokines [ 31 , 34 , 35 , 36 ]. Of note, cell death pathways (e.g., autophagy, NETosis, pyroptosis, apoptosis, necroptosis, and ferroptosis) in surrounding immune cells and stromal cells are activated, fueling the cytokine storm and cultivating a positive cell death-inflammation feedback loop [ 30 , 37 , 38 ].…”

Novel mechanisms of thrombo-inflammation during infection: the harmful impact of circulating histones

“…Ever increasingly important evidence highlights that histones (intranuclear positively charged proteins, associated with chromatin) show extranuclear/extracellular functions when extruded mainly by activated white blood cells and platelets during bacterial and viral infections [ 2 , 3 ]. In this respect, circulating histones have been demonstrated as inducers of cellular damage through cytotoxic proinflammatory effects, promoting monocyte activation and platelet aggregation, as well as finally acting as damage-associated molecular pattern molecules [ 2 ].…”