RETRACTED ARTICLE: High Systemic Levels of the Cytokine-Inducing HMGB1 Isoform Secreted in Severe Macrophage Activation Syndrome

RETRACTED ARTICLE: High Systemic Levels of the Cytokine-Inducing HMGB1 Isoform Secreted in Severe Macrophage Activation Syndrome

Molecular Medicine, September 2014

25247290

Karin Palmblad, Hanna Schierbeck, Erik Sundberg, Anna-Carin Horne, Helena Erlandsson Harris, Jan-Inge Henter, Daniel J. Antoine, Ulf Andersson

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by NK cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflammation as a prototypic alarmin. The redox states of its three cysteines render the molecule mutually exclusive functions: fully reduced all-thiol-HMGB1 exerts chemotactic activity, disulfide-HMGB1 cytokine-inducing, TLR4-mediated effects, while terminally oxidized sulfonyl-HMGB1 lacks inflammatory activity. This study examines the kinetic pattern of systemic HMGB1 isoform expression during therapy in four children with severe MAS. Three of the four patients with underlying systemic rheumatic diseases were treated with biologics and two suffered from triggering herpes virus infections at the onset of MAS. All patients required intensive care unit therapy due to life-threatening illness. Tandem mass-spectrometric analysis revealed dramatically increased systemic levels of predominantly the cytokine-inducing HMGB1 isoform during early MAS. Disease control coincided with supplementary etoposide therapy initiated to boost apoptotic cell death, when systemic HMGB1 levels drastically declined and the molecule emerged mainly in its oxidized, non-inflammatory isoform. Systemic IFN-γ and ferritin peaked concomitantly with HMGB1, whereas IL-18 and MCP-1 levels developed differently. In conclusion, this work provides new insights in HMGB1 biology, suggesting that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of disulfide-HMGB1 antagonists to improve outcome of MAS.