The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

Abstract

High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from posttranslational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells

“…HMGB1 is a well-known endogenous ligand of TLR4 that has the ability to trigger an inflammatory response [23][24][25]. HMGB1-TLR4 interaction results in downstream activation of NFκB, and subsequent inflammation via generation of PIC and reactive oxygen species [67].…”

“…The release of HMGB1 marks the initiation of host defense or inflammatory tissue repair mechanisms [21]. Receptor blocking studies have shown that HMGB1 is a strong endogenous ligand of TLR4 receptor [22][23][24][25]. TLR4 is a receptor found on the cell surface that mediates the proinflammatory effects [26,27] of its ligands through the NFkB signaling pathway.…”

Yeast HMO1: Linker Histone Reinvented

“…In mammalian cells, the nucleus contains approximately 1 HMGB protein for every 10 nucleosomes (90). In addition to roles in DNA-dependent events, HMGB proteins sense cellular stress and function as extracellular cytokines, contributing to inflammatory and immune responses (91).…”

HMGB1 expression patterns during the progression of experimental autoimmune encephalomyelitis

“…In this study, we detected the nuclear expression of HMGB1 in some of astrocytes, microglia and a few neurons in adult mouse spinal cord, which supplies more information to characterize the expression of HMGB1 in CNS and helps in discovering the potential CNS specific functions of HMGB1. Extracellular HMGB1, which is released passively by death cells or actively by stimulated cells such as macrophages, has been reported to play a key role in autoimmune diseases (Magna and Pisetsky, 2014), allograft rejection (Xia et al, 2014), ischemic stroke (Hayakawa et al, 2012), traumatic brain injury (Laird et al, 2014), and neurodegenerative diseases (Fang et al, 2012) as an inflammatory mediator. MS/EAE is a CNS specific autoimmune disease, which happens in adult human being or is induced in adult animal.…”