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Sickle cell disease increases high mobility group box 1: a novel mechanism of inflammation. Blood 2014 Dec 18;124(26):3978-81

Date

10/24/2014

Pubmed ID

25339362

Pubmed Central ID

PMC4271182

DOI

10.1182/blood-2014-04-560813

Scopus ID

2-s2.0-84919487296   24 Citations

Abstract

High mobility group box 1 (HMGB1) is a chromatin-binding protein that maintains DNA structure. On cellular activation or injury, HMGB1 is released from activated immune cells or necrotic tissues and acts as a damage-associated molecular pattern to activate Toll-like receptor 4 (TLR4). Little is known concerning HMGB1 release and TLR4 activity and their role in the pathology of inflammation of sickle cell disease (SCD). Circulating HMGB1 levels were increased in both humans and mice with SCD compared with controls. Furthermore, sickle plasma increased HMGB1-dependent TLR4 activity compared with control plasma. HMGB1 levels were further increased during acute sickling events (vasoocclusive crises in humans or hypoxia/reoxygenation injury in mice). Anti-HMGB1 neutralizing antibodies reduced the majority of sickle plasma-induced TLR4 activity both in vitro and in vivo. These findings show that HMGB1 is the major TLR4 ligand in SCD and likely plays a critical role in SCD-mediated inflammation.

Author List

Xu H, Wandersee NJ, Guo Y, Jones DW, Holzhauer SL, Hanson MS, Machogu E, Brousseau DC, Hogg N, Densmore JC, Kaul S, Hillery CA, Pritchard KA Jr

Authors

David Brousseau MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
John C. Densmore MD Professor in the Surgery department at Medical College of Wisconsin
Neil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anemia, Sickle Cell
Animals
Gene Expression Regulation
HMGB1 Protein
Humans
Hypoxia
Inflammation
Ligands
Mice
Mice, Inbred C57BL
Oxygen
Signal Transduction
Toll-Like Receptor 4
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a