High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells

• Published in: Seminars in immunology Vol. 38; no. C; pp. 40 - 48
• Main Authors: Andersson, Ulf, Yang, Huan, Harris, Helena
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2018
• Subjects: Alarmins; DAMPs; HMGB1; Inflammation; Medicin och hälsovetenskap; RAGE; Sepsis; TLR4; Trauma; Alarmins; Sepsis; Inflammation; HMGB1; RAGE; TLR4; Trauma; DAMPs
• ISSN: 1044-5323; 1096-3618; 1096-3618
• DOI: 10.1016/j.smim.2018.02.011

•TLR4 and RAGE are dominant HMGB1-receptors.•HMGB1 forms complexes with other inflammatory molecules which are endocytosed via RAGE.•Endocytosed HMGB1 destabilizes lysosomal membranes and the leaking lysosomes allow molecules access to cytosolic sensors.•LPS and nucleic acids need HMGB1 to express full toxicity.•HMGB1 blockade is of great clinical interest for multiple inflammatory conditions. Alarmins are preformed, endogenous molecules that can be promptly released to signal cell or tissue stress or damage. The ubiquitous nuclear molecule high-mobility group box 1 protein (HMGB1) is a prototypical alarmin activating innate immunity. HMGB1 serves a dual alarmin function. The protein can be emitted to alert adjacent cells about endangered homeostasis of the HMGB1-releasing cell. In addition to this expected path of an alarmin, extracellular HMGB1 can be internalized via RAGE-receptor mediated endocytosis to the endolysosomal compartment while attached to other extracellular proinflammatory molecules. The endocytosed HMGB1 may subsequently destabilize lysosomal membranes. The HMGB1-bound partner molecules depend on the HMGB1-mediated transport and the induced lysosomal leakage to obtain access to endosomal and cytosolic reciprocal sensors to communicate extracellular threat and to initiate the proper activation pathways.