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High-Mobility Group Box 1-Induced Complement Activation Causes Sterile Inflammation

 Sook Young Kim  ;  Myoungsun Son  ;  Sang Eun Lee  ;  In Ho Park  ;  Man Sup Kwak  ;  Myeonggil Han  ;  Hyun Sook Lee  ;  Eun Sook Kim  ;  Jae-Young Kim  ;  Jong Eun Lee  ;  Ji Eun Choi  ;  Betty Diamond  ;  Jeon-Soo Shin 
 Frontiers in Immunology, Vol.9 : 705, 2018 
Journal Title
 Frontiers in Immunology 
Issue Date
complement ; hepatotoxicity ; high-mobility group box 1 ; ischemia ; sterile inflammation
High-mobility group box 1 (HMGB1), a well-known danger-associated molecular pattern molecule, acts as a pro-inflammatory molecule when secreted by activated immune cells or released after necrotic cell damage. HMGB1 binds to immunogenic bacterial components and augments septic inflammation. In this study, we show how HMGB1 mediates complement activation, promoting sterile inflammation. We show that HMGB1 activates the classical pathway of complement system in an antibody-independent manner after binding to C1q. The C3a complement activation product in human plasma and C5b-9 membrane attack complexes on cell membrane surface are detected after the addition of HMGB1. In an acetaminophen (APAP)-induced hepatotoxicity model, APAP injection reduced HMGB1 levels and elevated C3 levels in C1q-deficient mouse serum samples, compared to that in wild-type (WT) mice. APAP-induced C3 consumption was inhibited by sRAGE treatment in WT mice. Moreover, in a mouse model of brain ischemia-reperfusion injury based on middle cerebral arterial occlusion, C5b-9 complexes were deposited on vessels where HMGB1 was accumulated, an effect that was suppressed upon HMGB1 neutralization. We propose that the HMGB1 released after cell necrosis and in ischemic condition can trigger the classical pathway of complement activation to exacerbate sterile inflammation.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실)
Yonsei Authors
곽만섭(Kwak, Man Sup)
박인호(Park, Inho)
신전수(Shin, Jeon Soo) ORCID logo https://orcid.org/0000-0002-8294-3234
이종은(Lee, Jong Eun) ORCID logo https://orcid.org/0000-0001-6203-7413
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