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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1207844

Received for publication December 19, 2007.
Revised June 16, 2008.
Accepted for publication June 17, 2008.

Article

Pivotal Advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis

Åsa Andersson *, Ruxandra Covacu *, Dan Sunnemark {dagger}, Alexandre I. Danilov *, Assunta Dal Bianco {ddagger}, Mohsen Khademi *, Erik Wallström *, Anna Lobell {sect}, Lou Brundin *, Hans Lassmann {ddagger}, and Robert A. Harris *@

*Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska University Hospital at Solna, Karolinska Institutet, Stockholm, Sweden; {dagger}Department of Molecular Sciences, Local Discovery Research Area CNS and Pain Control, AstraZeneca AB, Södertälje, Sweden; {ddagger}Center of Brain Research, Medical University of Vienna, Vienna, Austria; and {sect}Center for Autoimmunity and Inflammation, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

@ To whom correspondence should be addressed. E-mail: Robert.Harris{at}ki.se.


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Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors—receptor for advanced glycation end products, TLR2, and TLR4—was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-{gamma} stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.

Key Words: autoimmunity • DAMP • pathology • Toll-like receptor (TLR) • innate immunity


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