Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B‐crystallin
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| Titel: | Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B‐crystallin |
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| Autoren: | Wouter H. Gerritsen, Malika Bsibsi, Hendrikus Boddeke, Sandra Amor, Johannes M. van Noort, Bart J. L. Eggen, Markus Kipp, Inge R. Holtman, Paul van der Valk |
| Quelle: | Holtman, I R, Bsibsi, M, Gerritsen, W H, Boddeke, H W G M, Eggen, B J L, van der Valk, P, Kipp, M, van Noort, J M & Amor, S 2017, 'Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B-crystallin', GLIA, vol. 65, no. 3, pp. 460-473. https://doi.org/10.1002/glia.23104 |
| Verlagsinformationen: | Wiley, 2017. |
| Publikationsjahr: | 2017 |
| Schlagwörter: | Male, 0301 basic medicine, Time Factors, microglia, BRAIN-INJURY, NEUROINFLAMMATION, CYCLOOXYGENASE-2, Mice, 03 medical and health sciences, INFLAMMATION, TLR2, IMMUNE-RESPONSE, Animals, Humans, Gene Regulatory Networks, NETWORK, RNA, Messenger, alternative activation, Cells, Cultured, Parenchymal Tissue, 0303 health sciences, INTERLEUKIN-15, Dose-Response Relationship, Drug, HSPB5, Tumor Necrosis Factor-alpha, Macrophages, MULTIPLE-SCLEROSIS LESIONS, Brain, alpha-Crystallin B Chain, COX-2, Mice, Inbred C57BL, Gene Expression Regulation, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, Cyclooxygenase 2, CELLS, Cytokines, Microglia |
| Beschreibung: | 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 |
| Publikationsart: | Article |
| Sprache: | English |
| ISSN: | 1098-1136 0894-1491 |
| DOI: | 10.1002/glia.23104 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/28063173 https://www.ncbi.nlm.nih.gov/pubmed/28063173 https://onlinelibrary.wiley.com/doi/full/10.1002/glia.23104 https://pubmed.ncbi.nlm.nih.gov/28063173/ https://europepmc.org/abstract/MED/28063173 https://research.vumc.nl/en/publications/identification-of-highly-connected-hub-genes-in-the-protective-re http://onlinelibrary.wiley.com/doi/10.1002/glia.23104/abstract https://research.vumc.nl/en/publications/ed332972-7c32-4f2e-a479-2bf060882c33 |
| Rights: | Wiley Online Library User Agreement |
| Dokumentencode: | edsair.doi.dedup.....8f01bae4d1fb50620277028f1271e614 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | 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 |
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| ISSN: | 10981136 08941491 |
| DOI: | 10.1002/glia.23104 |