title: Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin.
abstract: Activated microglia and macrophages play a key role in driving demyelination during multiple sclerosis (MS), but the factors responsible for their activation remain poorly understood. Here, we present evidence for a dual-trigger role of IFN-γ and alpha B-crystallin (HSPB5) in this context. In MS-affected brain tissue, accumulation of the molecular chaperone HSPB5 by stressed oligodendrocytes is a frequent event. We have shown before that this triggers a TLR2-mediated protective response in surrounding microglia, the molecular signature of which is widespread in normal-appearing brain tissue during MS. Here, we show that IFN-γ, which can be released by infiltrated T cells, changes the protective response of microglia and macrophages to HSPB5 into a robust pro-inflammatory classical response. Exposure of cultured microglia and macrophages to IFN-γ abrogated subsequent IL-10 induction by HSPB5, and strongly promoted HSPB5-triggered release of TNF-α, IL-6, IL-12, IL-1β and reactive oxygen and nitrogen species. In addition, high levels of CXCL9, CXCL10, CXL11, several guanylate-binding proteins and the ubiquitin-like protein FAT10 were induced by combined activation with IFN-γ and HSPB5. As immunohistochemical markers for microglia and macrophages exposed to both IFN-γ and HSPB5, these latter factors were found to be selectively expressed in inflammatory infiltrates in areas of demyelination during MS. In contrast, they were absent from activated microglia in normal-appearing brain tissue. Together, our data suggest that inflammatory demyelination during MS is selectively associated with IFN-γ-induced re-programming of an otherwise protective response of microglia and macrophages to the endogenous TLR2 agonist HSPB5.
authors.affiliation: Delta Crystallon, Zernikedreef 9, 2333, CK Leiden, The Netherlands.
authors.forename: Malika
authors.initials: M
authors.lastname: Bsibsi
authors.forename: Laura A N
authors.initials: LA
authors.lastname: Peferoen
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nacken
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.forename: Maarten E
authors.initials: ME
authors.lastname: Witte
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
authors.forename: Johannes M
authors.initials: JM
authors.lastname: van Noort
mesh_terms: D001921:Brain / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000378:metabolism*
chemical_list: C059215:CRYAB protein, human; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; C573415:IFNG protein, human; C508609:IL10 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C109184:UBD protein, human; D014452:Ubiquitins; D038203:alpha-Crystallin B Chain; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D038362:Glycogen Synthase Kinase 3