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Review
. 2024 Aug 14:15:1438984.
doi: 10.3389/fimmu.2024.1438984. eCollection 2024.

Emerging therapeutic strategies _targeting extracellular histones for critical and inflammatory diseases: an updated narrative review

Tinghang Yang  1 , Jing Peng  1 , Zhuyun Zhang  1 , Yu Chen  2 , Zhihui Liu  3 , Luojia Jiang  4 , Lunqiang Jin  1 , Mei Han  1 , Baihai Su  1   5   6 , Yupei Li  1
Affiliations
Review

Emerging therapeutic strategies _targeting extracellular histones for critical and inflammatory diseases: an updated narrative review

Tinghang Yang et al. Front Immunol. .

Abstract

Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-_targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-_targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-_targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.

Keywords: blood purification; damage-associated molecular patterns; extracellular histones; heparin; histone-neutralization; inflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pathological roles of extracellular histones. (A) Histones induce hyperinflammation by activating the TLR 2/4/9 or NLRP3 inflammasome pathways, which results in the release of proinflammatory cytokines, such as IL-6, IL-1α, IL-8, IL-1β, IL-18, and TNF-α, calcium oscillation, and cell pyroptosis, and further augments innate immune cell recruitment in the blood. (B) Histones sense TLR-4 to induce endothelial dysfunction, which is characterized by endothelial glycocalyx degradation, intercellular adherents destruction and vascular leakage, ultimately leading to inflammatory exudation, tissue edema and organ failure. (C) Histones self-recognizing with TLR-2 and TLR-4 promote histone-mediated platelet activation and aggregation and thrombocytopenia in a platelet-dependent manner. The expression of tissue factor and Weibel-Palade bodies is further induced by activating endothelial cells, causing thrombosis. TLR, Toll-like receptor; NLRP3, NOD-like receptor family pyrin domain-containing 3; IL, interleukin; TNF, tumor necrosis factor; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule. This picture was generated using MedPeer software.
Figure 2
Figure 2
Mechanism of action of currently available anti-histone therapeutic strategies in preclinical studies. Extracellular histones exposed to the circulation induce the activation and aggregation of platelets, formation of clots, release of proinflammatory cytokines and recruitment and adhesion of innate immune cells, processes that can be inhibited by the use of histone-neutralizers, such as heparin and its heparinoids, polyanions, nanoparticles, hydrogels, monoclonal antibodies, RNA aptamers, plasma proteins (albumin, pentraxin-3, C-reactive protein, osteopontin, etc.), etc. Furthermore, various histone-interference strategies, including the promotion of histone degregation (FSAP, activated protein C, and GzmA) and extracorporeal blood purification for histone removal, decrease extracellular histone levels. Lesional histones induce barrier disintegrety, cell death and inflammatory reactions, processes that can be inhibited by related receptor blockers. Additionally, the inhibition of NET release by PAD4 inhibitors prevents the release of histones from neutrophils and reduces associated inflammation. Likewise, the administration of short-chain fatty acids and dexmedetomide lower histone levels in circulation. FSAP, factor VII-activating protease; GzmA, granzyme A; PAD4, peptidylarginine deiminase 4; TLR, toll-like receptor. This picture was generated using MedPeer software.
Figure 3
Figure 3
The chemical structure of CS-E 19-mer.
Figure 4
Figure 4
Chemical structures of mCBS (A) and MTS (B).
Figure 5
Figure 5
Chemical structure of suramin.
Figure 6
Figure 6
Chemical structure of defibrotide.
Figure 7
Figure 7
Chemical structure of HNPs.
See this image and copyright information in PMC

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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We acknowledge that this work is financially sponsored by the National Science Foundation of China (Grant No. 82300848 and U21A2098), the Sichuan Science and Technology Program (Grant No. 23NSFSC4038 and 22NSFSC3208), the Jiangxi Provincial Natural Science Foundation (Grant No. 20232BAB206031) and the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University (Grant No. ZYJC21010) and the Post-Doctor Research Project of West China Hospital, Sichuan University (Grant No. 2021HXBH084).

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