title: Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B-crystallin.
abstract: The glial stress protein alpha B-crystallin (HSPB5) is an endogenous agonist for Toll-like receptor 2 in CD14+cells. Following systemic administration, HSPB5 acts as a potent inhibitor of neuroinflammation in animal models and reduces lesion development in multiple sclerosis patients. Here, we show that systemically administered HSPB5 rapidly crosses the blood-brain barrier, implicating microglia as additional targets for HSPB5 along with peripheral monocytes and macrophages. To compare key players in the HSPB5-induced protective response of human macrophages and microglia, we applied weighted gene co-expression network analysis on transcript expression data obtained 1 and 4 h after activation. This approach identified networks of genes that are co-expressed in all datasets, thus reducing the complexity of the nonsynchronous waves of transcripts that appear after activation by HSPB5. In both cell types, HSPB5 activates a network of highly connected genes that appear to be functionally equivalent and consistent with the therapeutic effects of HSPB5 in vivo, since both networks include factors that suppress apoptosis, the production of proinflammatory factors, and the development of adaptive immunity. Yet, hub genes at the core of the network in either cell type were strikingly different. They prominently feature the well-known tolerance-promoting programmed-death ligand 1 as a key player in the macrophage response to HSPB5, and the immune-regulatory enzyme cyclooxygenase-2 (COX-2) in that of microglia. This latter finding indicates that despite its reputation as a potential target for nonsteroidal anti-inflammatory drugs, microglial COX-2 plays a central role in the therapeutic effects of HSPB5 during neuroinflammation. GLIA 2017;65:460-473.
authors.affiliation: Department of Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, the Netherlands.
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.affiliation: Delta Crystallon BV, Beverwijk, ED, the Netherlands.
authors.forename: Malika
authors.initials: M
authors.lastname: Bsibsi
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, HV, the Netherlands.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.affiliation: Department of Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, the Netherlands.
authors.forename: Hendrikus W G M
authors.initials: HW
authors.lastname: Boddeke
authors.affiliation: Department of Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, the Netherlands.
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, HV, the Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.affiliation: Department of Neuroanatomy, University of Munich, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kipp
authors.affiliation: Delta Crystallon BV, Beverwijk, ED, the Netherlands.|Department of Pathology, VU University Medical Center, Amsterdam, HV, the Netherlands.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: van Noort
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, HV, the Netherlands.|Department of Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D000072356:Parenchymal Tissue / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C059215:CRYAB protein, human; D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D038203:alpha-Crystallin B Chain; D051546:Cyclooxygenase 2
keywords: COX-2; HSPB5; TLR2; alternative activation; microglia