Systemic Release of High Mobility Group Box 1 Protein during Severe Murine Influenza

Abstract

Hypercytokinemia is gaining recognition as the mechanism of fatality from influenza. No work to date has addressed the role of high mobility group box 1 protein (HMGB1) in influenza, the parallel being that in other severe proinflammatory cytokine syndromes (e.g., sepsis and malaria) levels of circulating HMGB1 are elevated and may correlate with death. Using a commercially available ELISA for HMGB1, we found that HMGB1 was not increased in the plasma of influenza virus-infected mice (A/Japan/305/57) on day 7 post infection, about the time of peak mortality, and peak levels of HMGB1 in the plasma did not occur until relatively late in infection, on day 9 post infection. In keeping with the late peak of HMGB1 being unassociated with mortality, administration of ethyl pyruvate, which inhibits active secretion but not passive release of HMGB1, to influenza virus-infected mice, did not affect their survival. Further work is required to determine whether influenza virus infection induces passive release of HMGB1, and whether HMGB1 neutralization with a specific Ab would improve survival.

Anti-inflammative effect of glycyrrhizin on rat thermal injury via inhibition of high-mobility group box 1 protein

“…HMGB1 contains three conserved redox-sensitive cysteines (C23, C45, and C106); modification of these cysteines determines the bioactivity of extracellular HMGB1 [18]. HMGB1 can be passively released by necrotic cells, cells infected by viruses [19][20][21][22] or mycobacteria [23,24], and actively released by innate immune cells in respond to endogenous host stimuli or exogenous bacterial products [25], and serves as a signaling molecule involve in acute and chronic inflammatory injury by binding to the receptor for advanced glycation end-products (RAGE) or Toll-like receptors (TLR2, 4 and 9), which results in the activation of pro-inflammatory pathways and enhanced inflammatory injury [15]. Therefore, the anti-inflammatory strategies based on targeting HMGB1 is of significant experimental and clinical interests.…”

High-mobility group box family of proteins: ligand and sensor for innate immunity

“…Recent reports indicate that HMGB1 release is regulated by the inflammasome, a multiprotein oligomer that activates caspase-1 to promote the maturation of inflammatory cytokines interleukin (IL)-1b and IL-18 [27,28]. Second, it is released by dying cells; typically those undergoing necrosis [20,29].…”

Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis

“…LPS stimulates the release of early [e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β] and late [highmobility group box 1 protein (HMGB1)] proinflammatory cytokines. It is these host products that mediate damage (Wang et al 1999;Alleva et al 2008). However, therapies that target early inflammatory cytokines have not been clinically approved.…”