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Acta Neuropathol Commun. 2019 Jun 10;7(1):94. doi: 10.1186/s40478-019-0747-x.

Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain.

Kim SW1,2, Lee H2,3, Lee HK2,3, Kim ID2,3, Lee JK4,5.

Author information

1
Department of Biomedical Sciences, Inha University School of Medicine, Inchon, Republic of Korea.
2
Medical Research Center, Inha University School of Medicine, inha 100, Nam-Gu, Inchon, 22212, Republic of Korea.
3
Department of Anatomy, Inha University School of Medicine, inha 100, Nam-Gu, Inchon, 22212, Republic of Korea.
4
Medical Research Center, Inha University School of Medicine, inha 100, Nam-Gu, Inchon, 22212, Republic of Korea. jklee@inha.ac.kr.
5
Department of Anatomy, Inha University School of Medicine, inha 100, Nam-Gu, Inchon, 22212, Republic of Korea. jklee@inha.ac.kr.

Abstract

It has been reported that neutrophil extracellular traps (NETs) play important roles in non-infectious diseases. In ischemic stroke, neutrophils infiltrate damaged brain tissue soon after injury and aggravate inflammation. Using a rat permanent MCAO model, we showed citrullinated histone H3+ (CitH3, a marker of NETosis) induction in neutrophils in leptomeninges and in peripheral blood soon after MCAO. Entry of CitH3+ cells occurred through leptomeninges after 6 h of MCAO and these cells were observed in cerebral cortex from 12 h and subsequently in striatum. It is interesting to note that CitH3+ induction began in circulating neutrophils before they migrated to brain parenchyma and they were detected as intact or lysed form. High mobility group box 1 (HMGB1), a danger associated molecular pattern (DAMP) molecule, was accumulated massively in serum after permanent MCAO and plays a critical role in CitH3 inductions in neutrophils in brain parenchyma and in peripheral blood. Both the all-thiol and disulfide types of HMGB1 induced CitH3 via their specific receptors, CXCR4 and TLR4, respectively. Importantly, HMGB1 not only induced NETosis but was included as a part of the extruded NETs, and contribute to NETosis-mediated neuronal death. Therefore, it would appear a vicious cycle exists between neuronal cell death and NETosis and HMGB1 mediates detrimental effects exerted by this cycle. When NETosis was suppressed by a PAD inhibitor in MCAO animals, delayed immune cell infiltrations were markedly suppressed and damages in blood vessels were significantly mitigated. The study shows NETosis with the involvement of HMGB1 as a mediator in a vicious cycle aggravates inflammation and subsequent damage in the ischemic brain.

KEYWORDS:

HMGB1; Inflammation; MCAO; NETosis; Permanent ischemia

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