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

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.

Value of Extracellular High Mobility Group Box 1 (HMGB1) in the Clinical Context of Immune Thrombocytopenia

“…Certain drugs are reported to inhibit HMGB1, including TNF-alpha inhibitors, corticosteroids, chloroquine, statins, and anticancer drugs cisplatine, daunomycine, methothrexate, which show their action towards humoral, cellular immune response or both. Antiagregant clopidogrel, anticoagulants heparin, thrombomodulin, danaparoid, antithrombin and activated protein C are also demonstrated to inhibit HMGB1 expression, release or activity [2][3][4][5][6][7][8][9][10][11][12][13][14]24]. Though the number of patients in our cohort is limited, we observed a very good response to corticosteroids in patients who have high HMGB1 levels.…”

“…In septic conditions, HMGB1 can bind to pathogen associated pattern molecules of lipopolysaccharides and facilitate the activation of TLR2 and TLR4 mediated inflammation [7]. As such an ambidextrous molecule, HMGB1 is also connected with innate immunity with complement system through C1q and activates classical pathway in an antibody dependent manner [14].…”

Aberrant Expression of High Mobility Group Box Protein 1 in the Idiopathic Inflammatory Myopathies

“…This is consistent with evidence demonstrating HMGB1 to have pro-inflammatory properties and correlate with inflammatory disease activity. In addition to cytokine and chemokine properties, HMGB1 can activate the classical pathway of complement (Kim et al, 2018), where complement deposition is a key mediator of myonecrosis (Engel and Biesecker, 1982). It is conceivable that HMGB1 released from necrotic myofibres could trigger further local muscle cytolysis and perpetuate further damage in a self-sustaining process.…”

The role of inflammation in epileptogenesis

“…However, in the presence of severe or chronic insults with BBB breakdown, complement proteins are mainly synthesized by infiltrating peripheral immune cells. The activators of the complement system can be infection inducers, DAMPs (HMGB1), apoptotic cells, and necrotic cells [101,102]. Once activated, the complement system can activate microglia-mediated synaptic pruning [103], induce secretion of proinflammatory cytokines, and affect neuronal excitatory state [101].…”