Targeting Inflammation Driven by HMGB1

Abstract

High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damageassociated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

“…Trigger the generation of pro-inflammatory and pro-osteoclastic factors via positive feedback loop [109][110][111][112]114 FADD Trigger a caspase cascade; induce GCs-induced apoptosis 6,118 Sclerostin Promote osteocyte cells death upon unloading; inhibit bone formation 53,107,108 BNIP3 Promote cell death during hypoxia 60,62 CCN2 Promote osteocyte apoptosis upon excess mechanical stress 33,69 TNF-α Stimulate osteocyte apoptosis upon inflammation and cancer 92,115,116 Caspase-3 Regulate osteocyte apoptosis via physical interactions in mechanistic stimulus 27,127 CTSK Breakdown the bone matrix adjacent to the osteocyte; increase the size of the osteocyte lacunae and mineralization decrease vitality of osteocytes 23 DMP-1 Regulate osteocyte formation and phosphate homeostasis; involve in osteocytic apoptosis 29,84,154 Pyk2 Promote GCs-induced osteocytic apoptosis via focal adhesion 82 Panx-1 Promote fatigue-induced osteocytic apoptosis 160 Anti-apoptotic function SOD2 Suppress aging and loss of bone mass; decrease degeneration of the osteocyte LCN 24,61 AMPK Protects against Hcy-induced osteocyte apoptosis 96,101,102 NO Maintain osteocytic vitality by pulsatile fluid flow 44,54,100…”

The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies

“…During the inflammatory response, HMGB1 is secreted by macrophages, platelets, EC, and monocytes, as well as necrotic or damaged cells [48]. Disulfide HMGB1 binds together with myeloid differentiation factor-2 and TLR-4, determining the formation of a complex that triggers the inflammatory response [49,50]. In addition, HMGB1 deficient cellular lines show a reduced capacity to induce cytokines [51].…”

Platelets and Their Role in the Pathogenesis of Cardiovascular Events in Patients With Community-Acquired Pneumonia

“…Strategies targeting this pro-inflammatory protein have been the subject of a very recent review (184). Amongst others, these include pharmacological agents such as metformin that inhibit the translocation of HMGB1 from the nucleus to the cytosol that is likely to be most relevant to megakaryocytes, as well as direct targeting of the protein by monoclonal antibodies, such as m2G7 that target the interaction of HMGB1 with TLR4 and RAGE (184).…”