title: Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses.
abstract: The mechanisms whereby human glial cells modulate local immune responses are not fully understood. Interleukin-27 (IL-27), a pleiotropic cytokine, has been shown to dampen the severity of experimental autoimmune encephalomyelitis, but it is still unresolved whether IL-27 plays a role in the human disease multiple sclerosis (MS). IL-27 contribution to local modulation of immune responses in the brain of MS patients was investigated. The expression of IL-27 subunits (EBI3 and p28) and its cognate receptor IL-27R (the gp130 and TCCR chains) was elevated within post-mortem MS brain lesions compared with normal control brains. Moreover, astrocytes (GFAP(+) cells) as well as microglia and macrophages (Iba1(+) cells) were important sources of IL-27. Brain-infiltrating CD4 and CD8 T lymphocytes expressed the IL-27R specific chain (TCCR) implying that these cells could respond to local IL-27 sources. In primary cultures of human astrocytes inflammatory cytokines increased IL-27 production, whereas myeloid cell inflammatory M1 polarization and inflammatory cytokines enhanced IL-27 expression in microglia and macrophages. Astrocytes in postmortem tissues and in vitro expressed IL-27R. Moreover, IL-27 triggered the phosphorylation of the transcription regulator STAT1, but not STAT3 in human astrocytes; indeed IL-27 up-regulated MHC class I expression on astrocytes in a STAT1-dependent manner. These findings demonstrated that IL-27 and its receptor were elevated in MS lesions and that local IL-27 can modulate immune properties of astrocytes and infiltrating immune cells. Thus, therapeutic strategies targeting IL-27 may influence not only peripheral but also local inflammatory responses within the brain of MS patients.
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sénécal
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Deblois
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Diane
authors.initials: D
authors.lastname: Beauseigle
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Raphael
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Jonas
authors.initials: J
authors.lastname: Brandenburg
authors.affiliation: NeuroResource, UCL Institute of Neurology, University College London, London, WC1N 1PJ, England.
authors.forename: Jia
authors.initials: J
authors.lastname: Newcombe
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, H3A 2B4.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Moore
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, H3A 2B4.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Department of Neurosciences, Université De Montréal and CRCHUM Montreal, Quebec, Canada, H2X 0A9.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Arbour
mesh_terms: D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D017628:Microglia / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D018123:Receptors, Interleukin / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C112441:IL27RA protein, human; D007378:Interleukins; C464565:MYDGF protein, human; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: T lymphocytes; astrocytes; cytokine; microglia; neuroinflammation