High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome
Authors: Anna-Carin Horne
Ulf Andersson
Daniel J Antoine
Erik Sundberg
Hanna Schierbeck
Karin Palmblad
Helena Erlandsson Harris
Jan-Inge Henter
Journal: Molecular Medicine (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Macrophage activation syndrome; HMGB1; inflammation; alarmin; redox states
Affiliations: Unit of Pediatric Rheumatology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden., Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden., Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden., Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.

Abstract:  Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (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" has cytokine-inducing, toll-like receptor 4 (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 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, noninflammatory isoform. Systemic interferon (IFN)-γ and ferritin peaked concomitantly with HMGB1, whereas interleukin (IL)-18 and monocyte chemotactic protein (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. 

Retracted: No

PubPeer comments:
 Retraction Note to: High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome https: molmed.biomedcentral.com articles 10.1186 s10020-020-00263-2 The Editors-in-Chief have retracted this article (Palmblad et al. 2014) following an investigation by the University of Liverpool. The investigation concluded, based on the circumstances described below, that the data obtained by mass-spectrometry presented in Figs. 2u20135 are likely to be fraudulent and should not be relied upon. The investigation found no evidence that this mass-spectrometry was carried out on any University of Liverpool instrumentation from systematic examination of equipment logs. This does not exclude the fact that the mass-spectrometry may have been undertaken at another research center. However, they found no evidence that the mass-spectrometry was performed anywhere else or any financial audit trail to indicate that instrument time was paid for elsewhere. In addition to this, the mass-spectrometry technique to quantify HMGB-1 isoforms by mass-spectrometry has been unable to be reproduced at the Liverpool laboratories using either the supplied protocol or through adaptation of the protocols. Similar data in other publications investigated in this case, in which the institution has been able to assess primary data or which involve publication of assessable mass-spectra images, have demonstrated figure fabrication and fraudulent manipulation of data. The co-authors of the article were found by the investigation not to be complicit in any research misconduct, and they have been invited to resubmit a revised version of the manuscript for further peer review. More information on the university s investigation can be found on the university website (Further update on research misconduct investigation 2020). Dr. Karin Palmblad, Dr. Anna-Carin Horne, Dr. Helena Erlandsson Harris, Dr. Jan-Inge Henter and Dr. Ulf Andersson agree to this retraction. Dr. Hanna Schierbeck and Dr. Erik Sundberg have not responded to any correspondence from the editor publisher about this retraction. ,