title: Alpha-B-crystallin induces an immune-regulatory and antiviral microglial response in preactive multiple sclerosis lesions.
abstract: Microglial nodules are frequently observed in the normal-appearing white matter of multiple sclerosis (MS) patients. Previously, we have shown that these clusters, which we call "preactive MS lesions," are closely associated with stressed oligodendrocytes and myelin sheaths that contain markedly elevated levels of the small stress protein alpha-B-crystallin (HspB5). Here, we show that microglia in these lesions express the recently identified receptors for HspB5, that is, CD14, Toll-like receptor family 1 and 2 (TLR1 and TLR2), and several molecular markers of the microglial response to HspB5. These markers were identified by genome-wide transcript profiling of 12 primary human microglial cultures at 2 time points after exposure to HspB5. These data indicate that HspB5 activates production by microglia of an array of chemokines, immune-regulatory mediators, and a striking number of antiviral genes that are generally inducible by type I interferons. Together, our data suggest that preactive MS lesions are at least in part driven by HspB5 derived from stressed oligodendrocytes and may reflect a local attempt to restore tissue homeostasis.
authors.affiliation: From Delta Crystallon BV, Leiden (MB, JMvN); Department of Medical Physiology, University Medical Centre Groningen, Groningen (IRH, BJLE, EB); and Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands (WHG, PvdV, SA); and Department of Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom (SA).
authors.forename: Malika
authors.initials: M
authors.lastname: Bsibsi
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.forename: Erik
authors.initials: E
authors.lastname: Boddeke
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Johannes M
authors.initials: JM
authors.lastname: van Noort
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C059215:CRYAB protein, human; D018950:Lipopolysaccharide Receptors; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D038203:alpha-Crystallin B Chain