HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection

Abstract

A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death

“…Release of HMGB1 as a result of necrotic cell death during tissue damage is well established 25,26,40 and has been confirmed here for necrotic cardiomyocytes in vitro as well as in vivo after myocardial infarction. However, HMGB1 release from apoptotic cells has also been reported, including from staurosporine-treated Jurkat, U937 and HeLa cells.…”

“…22 It can be actively secreted by monocytes/macrophages, DC and other cells in response to pathogen-derived, pro-inflammatory or stress signals. [23][24][25] Moreover, HMGB1 is a prototypic damageassociated molecular pattern passively released from necrotic cells. 26 Although it may be released from apoptotic cells as well, 27 it appears to be preferentially retained in apoptotic bodies because of enhanced chromatin binding 26 and to be inactive due to oxidization of the crucial cysteine residues 23, 45 and 106, 28,29 which is critical for the tolerogenic nature of apoptotic cell death.…”

“…32 It recruits monocytes/ macrophages and DC to sites of tissue damage or infection and causes their activation, thereby mediating sterile, tissueinjury-driven as well as pathogen-driven inflammation and the initiation of adaptive immune responses. 25,33 Although the inflammatory processes initiated by HMGB1 appear to be detrimental to tissue regeneration, 25,34 pro-angiogenic activities of HMGB1 35 as well as recruitment of stem and progenitor cells 36,37 may have beneficial effects after tissue damage.…”

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

“…Extracellular HMGB1 interacts with cell surfaceexpressed receptors: RAGE, TLR2 and TLR4, which promote the activation of the MyD88-mediated NF-kB pathway. 7,[32][33][34] HMGB1 or HMGB2 released from necrotic cells can exert a proinflammatory effect by transmitting a damage signal to neighboring cells. 35,36 In the cytoplasm, HMGBs bind immunogenic nucleotides and deliver them to the cytosolic nucleic acid sensors retinoic acid-inducible gene I, MDA5, AIM2 and DAI and to the endosome nucleic acid-sensing TLRs (TLR3, TLR7 and TLR9).…”

Tissue damage negatively regulates LPS-induced macrophage necroptosis

“…7 During tissue injury, HMGB1 is released from cells and serves as a necessary and sufficient mediator of inflammation to induce a variety of cellular responses including cell chemotaxis and the release of pro-inflammatory cytokines. 8,9 Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4, and TLR9.…”