title: Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis.
abstract: Similar to macrophages, microglia adopt diverse activation states and contribute to repair and tissue damage in multiple sclerosis. Using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, we show that in vitro M1-polarized (proinflammatory) human adult microglia express the distinctive markers CD74, CD40, CD86, and CCR7, whereas M2 (anti-inflammatory) microglia express mannose receptor and the anti-inflammatory cytokine CCL22. The expression of these markers was assessed in clusters of activated microglia in normal-appearing white matter (preactive lesions) and areas of remyelination, representing reparative multiple sclerosis lesions. We show that activated microglia in preactive and remyelinating lesions express CD74, CD40, CD86, and the M2 markers CCL22 and CD209, but not mannose receptor. To examine whether this intermediate microglia profile is static or dynamic and thus susceptible to changes in the microenvironment, we polarized microglia into M1 or M2 phenotype in vitro and then subsequently treated them with the opposing polarization regimen. These studies revealed that expression of CD40, CXCL10, and mannose receptor is dynamic and that microglia, like macrophages, can switch between M1 and M2 phenotypic profiles. Taken together, our data define the differential activation states of microglia during lesion development in multiple sclerosis-affected CNS tissues and underscore the plasticity of human adult microglia in vitro.
authors.affiliation: From the Departments of Pathology (LANP, DYSV, KU, WHG, RMBP-B, PvdV, SA) and Molecular Cell Biology and Immunology (DYSV, MB, PDAMH, CDD), VU University Medical Center, Amsterdam, The Netherlands; and Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine Dentistry, Queen Mary University of London, London, United Kingdom (SA).
authors.forename: Laura A N
authors.initials: LA
authors.lastname: Peferoen
authors.forename: Daphne Y S
authors.initials: DY
authors.lastname: Vogel
authors.forename: Kimberley
authors.initials: K
authors.lastname: Ummenthum
authors.forename: Marjolein
authors.initials: M
authors.lastname: Breur
authors.forename: Priscilla D A M
authors.initials: PD
authors.lastname: Heijnen
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.forename: Regina M B
authors.initials: RM
authors.lastname: Peferoen-Baert
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Christine D
authors.initials: CD
authors.lastname: Dijkstra
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D059467:Transcriptome
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger