In the review of this issue,1 the authors have illustrated and summarized the findings and knowledge of how the high-mobility group box 1 protein (HMGB1) mediates in acute and chronic organ injuries. HMGB1 is a ubiquitously expressed nuclear factor. It is an important mediator of inflammation through receptors of the innate immune system. The inflammatory nature of organ and tissue injury from chemical or physical stress makes HMGB1 a crucial factor in the pathogenesis of acute and chronic diseases and injury. This review article is clear and helpful for the readers working in the same field. Recently, the discoveries of receptors involved in HMGB1 mediated organ injury have also led to α2 adrenergic receptor inhibition by dexmedetomidine and electroacupuncture for α7nAChR attenuation to decrease inflammation.2, 3 Furthermore, using soluble levels of receptor for advanced glycation endproducts (RAGE) to compete for HMGB1-dependent RAGE activation has also been shown to decrease organ injury.4 However, HMGB1 is an important mediator in inflammation through receptors of the innate immune system. There are many unsolved problems and new challenges to emerge.
1. HMGB1 and its physiological and pathological roles
Lately, HMGB1 participation in innate and specific immune responses has been revealed. Passively released from necrotic cells or actively produced by various cell types, HMGB1 acts as an alarmin and is responsible for production of proinflammatory cytokines. HMGB1 is able to interact with RAGE and toll-like receptors (TLRs), receptors that belong to family of pattern recognition receptors and are involved in activation of pathways leading to production of proinflammatory cytokines. Its key role has been revealed in mediation of sepsis and as it is released later than other proinflammatory cytokines, it has become known as a “late mediator of sepsis”. HMGB1 also contributes to the development of athersclerosis and autoimmune diseases; for example, its association with immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis has been suggested. In addition to its negative function, HMGB1 protein seems to be able to attract stem cells to the area of inflammation and thus promote regeneration processes. This paradoxical function of HMGB1 protein has also been revealed in growth and spread of many types of tumors. HMGB1 represents a potential target in therapy of various disorders related to inflammation.5
2. HMGB1 signaling and inflammation
As now recognized, HMGB1 has a broad repertoire of immunological activities that encompasses induction of cytokine production, cell proliferation, chemotaxis, angiogenesis, and cell differentiation. In addition to effects on immune cells, HMGB1 can modulate the activities of hematopoietic, epithelial, and neuronal cells, and mediate systemic effects such as fever, anorexia, and acute-phase responses. These activities reflect its function as an alarmin and its ability to engage diverse receptors including TLR2, TLR4, TLR9, RAGE, and CD24-Siglec-10 (Siglec-G in in mice). In these interactions, post-translational modifications of HMGB1, including acetylation, phosphorylation, methylation and redox changes of cysteine residues, can influence the receptor interactions and downstream signaling events.6, 7, 8, 9, 10
3. Blockade of HMGB1 as therapy
At present, clinical studies using HMGB1-specific antagonists have not been performed in patients, although this approach is effective in preclinical animal models of diverse conditions including sepsis, arthritis, stroke, organ transplantation, and acetaminophen-induced hepatotoxicity. Therapy based on the use of the recombinant A box domain of HMGB1 has also been successful, although the mechanism is unknown. Of note, small molecules can also antagonize HMGB1 by blocking its release from cells, with metformin, for example, inhibiting the release of HMGB1 from a macrophage cell line as well as increasing survival in mice treated with lipopolysaccharide. The setting of sepsis is especially informative and suggests unique effects of inhibiting HMGB1. Administration of anti-HMGB1 antibodies or recombinant A box protein in mice with polymicrobial Gram-negative sepsis from cecal ligation and perforation substantially improves survival even when treatment is started late in disease. By contrast, anti-tumor necrosis factor (TNF) antibodies worsen survival in this model, highlighting important differences between the roles of HMGB1 and TNF in pathogenesis. Whether HMGB1 blockade in arthritis provides any advantage when compared with TNF neutralization is presently unknown as the models studies are dependent on TNF as well as HMGB1.6, 7, 11
4. Conclusion
In conclusion, the study of HMGB1 and its signaling pathways continue to increase possibilities in drug design and therapy to prevent/treat organ injury in the future.