Abstract
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.
Highlights
High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule located in the nucleus that is secreted from activated monocytes/macrophages and released from necrotic cells [1]
Treatment with HMGB1 protein by itself has a weak proinflammatory activity in vitro [16, 21], it is a potent effector of inflammation when released in vivo, suggesting that it works with other factors [40] or upregulates pro-inflammatory processes in vivo
The release of BCECF into the supernatant was increased by the addition of HMGB1 to 20% Normal human serum (NHS) (Figure S1C in Supplementary Material). These results suggest that HMGB1 may cause vascular permeability and blood–brain barrier (BBB) disruption in brain ischemia by promoting complement activation, consistent with our data and those described in a previous study [45]
Summary
High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule located in the nucleus that is secreted from activated monocytes/macrophages and released from necrotic cells [1]. Extracellular HMGB1 alone binds to Toll-like receptor (TLR) 2, TLR4, and RAGE and activates nuclear factor (NF)-κB and extracellular signal-regulated kinase (ERK) 1/2 [11,12,13], thereby inducing sterile inflammation [14, 15]. HMGB1 can bind to pathogen-associated molecular pattern (PAMP) molecules of lipopolysaccharide (LPS) or lipoteichoic acid (LTA) and facilitate their transfer to CD14, resulting in TLR4- or TLR2-mediated inflammation [16, 17]. HMGB1 acts as a pro-inflammatory cytokine mediator of sepsis; it induces a weak tumor necrosis factor (TNF)-α production in in vitro treatments [21]. The mechanism of HMGB1-mediated inflammation, as a DAMP molecule-mediated process in vivo, remains to be delineated
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