HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease

Abstract

HMGB1 is a non-histone nuclear protein that can serve as an alarmin to drive the pathogenesis of inflammatory and autoimmune disease. Although primarily located in the cell nucleus, HMGB1 can translocate to the cytoplasm, as well as the extracellular space, during cell activation and cell death; during activation, HMGB1 can undergo post-translational modifications. The activity of HMGB1 varies with the redox states of the cysteine residues, which are required for binding to TLR4. In addition to stimulating cells directly, HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous factors. In the synovia of patients with rheumatoid arthritis, as well as animal models of this disease, extranuclear expression of HMGB1 is increased and blockade of HMGB1 expression attenuates disease in animal models. In systemic lupus erythematosus, HMGB1 can be a component of immune complexes containing anti-DNA because of its interaction with DNA. In myositis, expression of HMGB1 is enhanced in inflamed muscle and can perturb muscle function. Together, these findings indicate that HMGB1 might be an important mediator and biomarker in rheumatic diseases as well as a target of new therapy.

Critical role of RAGE and HMGB1 in inflammatory heart disease

“…Several studies point out the activation of RAGE by HMGB1 (7,24). Altered protein levels of RAGE isoforms in patients suffering from heart failure also refer to the clinical relevance of this pathway (16,18,19).…”

“…HMGB1 can be either actively secreted or passively released into the extracellular milieu upon cell death (7). Upon reaching the extracellular environment, HMGB1 acts as a DAMP, activating TLRs and RAGE, which in turn can promote an immune response (24,25).…”

Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

“…The biological and clinical importance of HMGB1 is underscored by the dysregulation of this protein in a number of pathological conditions, including sepsis, ischemia-reperfusion injury, arthritis, and cancer (1,(3)(4)(5). Nonetheless, in vivo validation of the versatile functions described above is lacking due to the lethality of the Hmgb1-deficient mice, thought to cause lethal hypoglycemia in newborn mice (25).…”

“…The release of HMGB1 is also regulated by the inflammasome, a multiprotein oligomer that activates caspase-1 to promote the maturation of inflammatory cytokines, interleukin-1β (IL-1β) and IL-18, and by dying cells, typically those undergoing necrosis (7)(8)(9)(10). Secreted or released, HMGB1 is known to participate in the activation of cell surface innate immune receptors, typically Toll-like receptors (TLRs), thereby affecting many aspects of the host's inflammatory responses upon infection or noxious stresses (1)(2)(3)(4)(5). Perhaps most notably is the crucial role of HMGB1 in LPS-induced endotoxemia, whereby administration of an anti-HMGB1 antibody significantly protects mice from lethality (1,11).…”

“…O f the four members of the high-mobility group box (HMGB) family, HMGB1 is the best studied, given its versatile functions in various aspects of cellular responses (1)(2)(3)(4)(5). Ubiquitously expressed in all cells, HMGB1 is found en masse in the nucleus and is supposedly released into the extracellular fluid through an endoplasmic reticulum-Golgi pathway-independent mechanism from immune cells such as monocytes or macrophages after stimulation with lipopolysaccharide (LPS), proinflammatory cytokines, or nitric oxide (1,6).…”