Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis.
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.
Andersson
Asa
A
Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska University Hospital at Solna, Karolinska Institutet, Stockholm, Sweden.
Covacu
Ruxandra
R
Sunnemark
Dan
D
Danilov
Alexandre I
AI
Dal Bianco
Assunta
A
Khademi
Mohsen
M
Wallström
Erik
E
Lobell
Anna
A
Brundin
Lou
L
Lassmann
Hans
H
Harris
Robert A
RA
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000473:pathology; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008264:Macrophages / Q000166:cytology; D017628:Microglia / Q000166:cytology; D009103:Multiple Sclerosis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology
D024243:HMGB1 Protein; D012333:RNA, Messenger