HMGB1 의 저밀도 지질단백질과의 결합으로 인한 상호작용 및 대식세포로의 uptake 에 미치는 영향

Atherosclerosis is an inflammatory cardiovascular disease which is commonly described as lipid accumulation in the intimal region of the arterial wall that eventually causes myocardial infarction and stroke. The high mobility group box 1 (HMGB1) is a nuclear protein which plays important role in immunity and inflammation. HMGB1 is elevated in atherosclerotic lesions which indicated its possible involvement in the progression of atherosclerosis. In this study, we observed that HMGB1 directly binds to LDL and modified LDL, but not to HDL. Moreover, modified LDL uptake by THP-1 macrophages was increased time- and dose-dependent manner in the presence of HMGB1. Addition of soluble CD36 scavenger receptor protein reversed the HMGB1 effect on modified LDL uptake. Further, HMGB1 bound to CD36 and CD36 overexpression enhanced the HMGB1 effect on modified LDL uptake. Collectively, our data indicates that HMGB1 bound to modified LDL and increased their uptake by macrophage through CD36 scavenger receptor.open석

Peroxiredoxin-mediated disulfide bond formation is required for nucleocytoplasmic translocation and secretion of HMGB1 in response to inflammatory stimuli

© 2019 The Authors The nuclear protein HMGB1 (high mobility group box 1) is secreted by monocytes-macrophages in response to inflammatory stimuli and serves as a danger-associated molecular pattern. Acetylation and phosphorylation of HMGB1 are implicated in the regulation of its nucleocytoplasmic translocation for secretion, although inflammatory stimuli are known to induce H 2 O 2 production. Here we show that H 2 O 2 -induced oxidation of HMGB1, which results in the formation of an intramolecular disulfide bond between Cys 23 and Cys 45 , is necessary and sufficient for its nucleocytoplasmic translocation and secretion. The oxidation is catalyzed by peroxiredoxin I (PrxI) and PrxII, which are first oxidized by H 2 O 2 and then transfer their disulfide oxidation state to HMGB1. The disulfide form of HMGB1 showed higher affinity for nuclear exportin CRM1 compared with the reduced form. Lipopolysaccharide (LPS)–induced HMGB1 secretion was greatly attenuated in macrophages derived from PrxI or PrxII knockout mice, as was the LPS-induced increase in serum HMGB1 level