Role of HMGB1 in the Interplay between NETosis and Thrombosis in Ischemic Stroke: A Review

Abstract

Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to the fact that the NETs serve as a scaffold for cells and numerous coagulation factors and stimulate fibrin deposition. A crosstalk between NETs and thrombosis has been indicated to play a role in numerous thrombosis-related conditions including stroke. In cerebral ischemia, neutrophils are the first group of cells to infiltrate the damaged brain tissue, where they produce NETs in the brain parenchyma and within blood vessels, thereby aggravating inflammation. Increasing evidences suggest the connection between NETosis and thrombosis as a possible cause of “tPA resistance”, a problem encountered during the treatment of stroke patients. Several damage-associated molecular pattern molecules have been proven to induce NETosis and thrombosis, with high mobility group box 1 (HMGB1) playing a critical role. This review discusses NETosis and thrombosis and their crosstalk in various thrombosis-related diseases, focusing on the role of HMGB1 as a mediator in stroke. We also addresses the function of peptidylarginine deiminase 4 with respect to the interplay with HMGB1 in NET-induced thrombosis.

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

“…It can be passively released from necrotic cells such as neurons and enter the extracellular milieu by simple diffusion (Scaffidi et al, 2002). Furthermore, HMGB1 is actively secreted in the extracellular medium by certain cells such as microglia, macrophages/monocytes, and neutrophils (Gardella et al, 2002;Tang et al, 2007a;Xiong et al, 2016;Sun et al, 2019;Kim and Lee, 2020). Recent studies have shown that HMGB1 is also released through extracellular vesicles such as exosomes derived from cultured astrocytes (Ma et al, 2019).…”

“…In a rat permanent MCAO model, citrullinated histone H3 + (CitH3, a marker of NETosis) induction in neutrophils in leptomeninges was observed soon after MCAO. HMGB1, as a NETosis inducer in the ischemic brain, contributes to NETosis-mediated neuronal death and aggravates inflammation and subsequent brain tissue damage in ischemic stroke (Kim et al, 2019b;Kim and Lee, 2020).…”

MicroRNAs as New Regulators of Neutrophil Extracellular Trap Formation

“…Interestingly, miR-505 has been tightly linked to high mobility group box 1 protein (HMGB1) expression in different types of cancer [ 74 , 75 ]. How this regulatory pathway may also play a role in NET formation in a cardiovascular context given the essential function of HMGB1 in NETosis may be a point of interest for future studies [ 76 ].…”

Neutrophil Extracellular Traps in Coronavirus Disease-19-Associated Ischemic Stroke: A Novel Avenue in Neuroscience

“…As high levels of neutrophils identified in cerebral thromboemboli, it brings out a suspicion about the contribution of NETs in thrombogenesis and its role in decreasing efficacy of intravenous thrombolysis among Acute Ischemic Stroke (AIS) patients [ 41 ]. The neutrophils being the first blood-borne immune cells to arrive at ischemic brain tissues, binding various adhesion molecules in order to attaching themselves to endothelium within 15 minutes of ischemic stroke [ 42 , 43 ], produces proinflammatory cytokines, chemokines, and cytotoxic molecules that accelerate the progression of brain damage [ 44 ]. It has known that the recruitment of neutrophils into the brain was orchestrated by IL-1.…”

“…The mechanism of NETs-induced neuro inflammation seems to correlate with the action of neutrophil granules-derived enzymes along with its inflammatory events. In the brain parenchyma, extruded NETs components induce brain damage [ 44 ]. Allen et al identified cathepsin-G and NE as the culprits of neuronal toxicity, and their inhibitors, when administered as a mixture, reported to reverse the neurotoxic effects of neutrophil.…”