High‐mobility group box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair

Abstract

Summary A single protein, HMGB1, directs the triggering of inflammation, innate and adaptive immune responses, and tissue healing after damage. HMGB1 is the best characterized damage‐associated molecular pattern (DAMP), proteins that are normally inside the cell but are released after cell death, and allow the immune system to distinguish between antigens that are dangerous or not. Notably, cells undergoing severe stress actively secrete HMGB1 via a dedicated secretion pathway: HMGB1 is relocated from the nucleus to the cytoplasm and then to secretory lysosomes or directly to the extracellular space. Extracellular HMGB1 (either released or secreted) triggers inflammation and adaptive immunological responses by switching among multiple oxidation states, which direct the mutually exclusive choices of different binding partners and receptors. Immune cells are first recruited to the damaged tissue and then activated; thereafter, HMGB1 supports tissue repair and healing, by coordinating the switch of macrophages to a tissue‐healing phenotype, activation and proliferation of stem cells, and neoangiogenesis. Inevitably, HMGB1 also orchestrates the support of stressed but illegitimate tissues: tumors. Concomitantly, HMGB1 enhances the immunogenicity of mutated proteins in the tumor (neoantigens), promoting anti‐tumor responses and immunological memory. Tweaking the activities of HMGB1 in inflammation, immune responses and tissue repair could bring large rewards in the therapy of multiple medical conditions, including cancer.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…Within the class of protein DAMPs, we could detect high levels of HMGB1, HSP70, and S100A8/A9 in the supernatants of irradiated tumor cells. All of them are known to be potent mediators of endothelial cell activation as well as recruitment and differentiation of APCs, 54–56 and they exert their functions via common receptors, including TLR4, the TLR2/4 dimer, RAGE, and members of the scavenger receptor family. 57–59 Accordingly, protein DAMP-stimulated TLR4-signaling has been reported to be essential for anti-tumor immune priming in the context of radiation and chemotherapy.…”

Nanotherapy in Joints: Increasing Endogenous Hyaluronan Production by Delivering Hyaluronan Synthase 2

“…[33,34] After treated with MSN-CC-PEI + HAS2, the intracellular HAS2 levels were significantly increased and a dose-dependent effect was observed ( Figure 3C,D). In addition, the upregulated inflammation-associated protein, high mobility group box 1 (HMGB1) [35,36] in OA synoviocytes was decreased by MSN-CC-PEI + HAS2 ( Figure S7, Supporting Information), indicating the suppression of cellular inflammation. The intracellular delivery of HAS2 has no www.advmat.de www.advancedsciencenews.com effect on the level of HA receptor CD44.…”

Ectodomain Shedding of RAGE and TLR4 as a Negative Feedback Regulation in High-Mobility Group Box 1-Activated Aortic Endothelial Cells

“…and increases the expression of adhesion molecules and the secretion of chemokines [24], while HMGB1 binding to CXCR4 potentiates chemotactic activity [23,24]. HMGB1 binding to TLR4 activates NF-κB and increases the transcription and secretion of inflammatory mediators [24].…”

“…HMGB1 binding to TLR4 activates NF-κB and increases the transcription and secretion of inflammatory mediators [24]. HMGB1 may also undergo oxidative modifications by reactive oxygen species and lose its immune function [23].…”

“…The reason is not clear, but it was assumed that both HMGB1 and LPS activate TLR4 by binding to MD-2, but to separate MD-2 epitopes, and thereby may activate different downstream signaling pathways [30]. It may also be because HMGB1 has lower affinity for TLR4 than LPS [24].…”