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.
Bibliographical noteFunding Information:
We thank Dr. J. H. Youn, Mrs. S. I. Yeon, Ms. Y. Ji, and Mr. H. S. Kim for their technical assistance.This work was supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (Nos. 2014R1A4A1008625, 2017R1A2B3006704, and 2016R1A2B4009438), the Research Center Program of Institute for Basic Science (IBS) in Korea (IBS-R026-D1), and Brain Korea 21 PLUS Project for Medical Science. This work was also supported by the National Institutes of Health [K01AR065506 (MS); P01 AI073693 (BD)]
© 2018 Kim, Son, Lee, Kwak, Han, Lee, Park, Kim, Kim, Lee, Choi, Diamond and Shin.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy