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Modulation of HMGB1 Release for Treating Lethal Infection and Injury

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Severe Trauma and Sepsis

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Abstract

Sepsis refers to a life-threatening organ dysfunction caused by a dysregulated host response to infection. Its pathogenesis is partly attributable to dysregulated inflammatory responses orchestrated by innate immune cells (e.g., macrophages and monocytes) that sequentially release early (e.g., TNF, IL-1, and IFN-γ) and late (e.g., HMGB1) pro-inflammatory mediators. As a ubiquitous nuclear protein, HMGB1 is constitutively expressed and can be actively secreted in response to exogenous pathogen-associated molecular pattern molecules (PAMPs, e.g., ds-RNA, CpG-DNA, and endotoxin) or endogenous cytokines [e.g., interferon (IFN)-γ or IFN-β]. In addition to active secretion, HMGB1 can also be passively released from damaged cells following ischemia/reperfusion, trauma, or toxemia, thereby serving as damage-associated molecular pattern (DAMP). Even during microbial infections, the PAMP-elicited inflammatory response may be accompanied by cell injury and DAMP release that further amplifies the cytokine storm to precipitate organ dysfunction. Here we discuss the evidence that support extracellular HMGB1 as a key mediator of inflammatory diseases and discuss the potential of several HMGB1-targeting therapies in animal models of lethal sepsis. Although microbial infection-induced sepsis is indistinguishable from sterile injury-elicited systemic inflammatory response syndrome, it may be more advantageous to develop strategies that specifically attenuate DAMP-mediated inflammatory responses without compromising the PAMP-mediated innate immunity.

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Acknowledgments and Funding

The work in authors’ laboratory was supported by grants from the US National Center of Complementary and Alternative Medicine (NCCAM, R01AT005076) and the US National Institute of General Medical Sciences (NIGMS, R01GM063075 and R41GM123858).

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Author notes

  1. Author contributed equally with all other contributors.Weiqiang Chen, Li He and Hui Jin

Authors and Affiliations

  1. Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY, USA

    Weiqiang Chen, John D’Angelo & Haichao Wang

  2. The Feinstein Institute for Medical Research, Manhasset, NY, USA

    Weiqiang Chen, Hui Jin, Guoqiang Bao & Haichao Wang

  3. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Li He

  4. Department of General Surgery, Tangdu Hospital, The 4th Military Medical University, Xi’an, Shaanxi, P. R. China

    Guoqiang Bao

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  1. Weiqiang Chen
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Correspondence to Haichao Wang .

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  1. Wound Healing and Cell Biology Lab, First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China

    Xiaobing Fu

  2. State Key Laboratory of Trauma, Burns, and Combined Injury, Daping Hospital, Third Military Medical University, Chong Qing, China

    Liangming Liu

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Chen, W., He, L., Jin, H., D’Angelo, J., Bao, G., Wang, H. (2019). Modulation of HMGB1 Release for Treating Lethal Infection and Injury. In: Fu, X., Liu, L. (eds) Severe Trauma and Sepsis. Springer, Singapore. https://doi.org/10.1007/978-981-13-3353-8_14

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