Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release

Abstract

HMGB1 orchestrates leukocyte recruitment and their induction to secrete inflammatory cytokines by switching between mutually exclusive redox states.

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

“…Indeed, fr-HMGB1 has a relatively short half-life (∼17 min) in biological fluids such as serum and saliva [37]. Other studies support this hypothesis and our findings are in agreement with these investigations [6, 16, 32, 38]. Lian et al [32] observed similar cytokine production and depressive-like behaviour after intracerebroventricular injection of either ds- or fr-HMGB1, and these effects were mediated via TLR4 and not RAGE or CXCL12, the receptors for fr-HMGB1.…”

“…In the present study we aimed to dissect the contribution of extracellular, cerebral HMGB1, in its disulfide or fully reduced redox form, to neuroinflammation. We did not include ox-HMGB1 as to date this redox form has not been found to mediate any pro-inflammatory function in vivo [4, 6] . Our results clearly demonstrate that ds- and fr-HMGB1 function as pro-inflammatory mediators in the CNS, promoting BBB disruption and cytokine production.…”

“…The best characterised of these include toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) [4, 5]. The ability of HMGB1 to interact with multiple unrelated receptors to induce diverse functions is tightly regulated by post-translational redox modification of the three cysteine residues at positions 23, 45, and 106 in the box A and B domains [4, 6]. Three different redox isoforms, with distinct functions, have been detected in vivo: (1) fully reduced HMGB1 (fr-HMGB1), with a thiol group present on each of the cysteine residues, induces cell migration, (2) disulfide HMGB1 (ds-HMGB1), containing a disulfide bridge between C23 and C45 and a reduced C106 residue, is a TLR4 ligand, and (3) sulphonyl HMGB1 (ox-HMGB1), where all cysteine residues are terminally oxidised, appears to have lost proinflammatory features and cannot induce cell migration or cytokine production.…”

“…The formation of a heterocomplex between fr-HMGB1 and CXCL12 has been detected in vitro using NMR and surface plasmon resonance analysis and in vivo after muscle tissue injury. fr-HMGB1-CXCL12 complexes interact with the chemokine receptor CXCR4 to promote cell migration in a TLR4- and RAGE-independent manner [6, 8]. …”

The Analysis of the Effective Systemic Lidocaine Dosage on the Expression of HMGB1 mRNA on Mice with Sterile Musculoskeletal Injury

“…Lidocaine also has anti-arrythmic and anti-inflammation properties. In the last decades, the anti-inflammation property of lidocaine had been used to treat septic mice and protect against organ failure from its ability to inhibit the expression of macrophage HMGB1 [11]- [16].…”