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Differentiation of primary adult microglia alters their response to TLR8-mediated activation but not their capacity as APC

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Author: Zuiderwijk-Sick, E.A. · Putten, C. van der · Bsibsi, M. · Deuzing, I.P. · Boer, W. de · Persoon-Deen, C. · Kondova, I. · Boven, L.A. · Noort, J.M. van · Hart, B.A. 't · Amor, S. · Bajramovic, J.J.
Type:article
Date:2007
Institution: TNO Defensie en Veiligheid TNO Kwaliteit van Leven
Source:GLIA, 15, 55, 1589-1600
Identifier: 240292
doi: doi:10.1002/glia.20572
Keywords: Health · Biomedical Research · Cell differentiation · Innate immune system · Monocytes/macrophages · Neuroimmunology · messenger RNA · toll like receptor 1 · toll like receptor 2 · toll like receptor 3 · toll like receptor 4 · toll like receptor 5 · toll like receptor 6 · toll like receptor 7 · toll like receptor 8 · toll like receptor 9 · transfer RNA · animal cell · antigen expression · antigen presentation · antigen presenting cell · article · cell differentiation · cell ultrastructure · colony forming unit GM · colony forming unit M · controlled study · cytokine production · innate immunity · microglia · mixed lymphocyte reaction · neuroimmunology · nonhuman · phagocyte · phenotype · priority journal · rhesus monkey · Animals · Antigen-Presenting Cells · Bone Marrow Cells · Cell Differentiation · Cell Lineage · Cell Proliferation · Cell Separation · Enzyme-Linked Immunosorbent Assay · Female · Flow Cytometry · Granulocyte-Macrophage Colony-Stimulating Factor · Lymphocyte Culture Test, Mixed · Macaca mulatta · Macrophage Activation · Macrophage Colony-Stimulating Factor · Male · Microglia · Phagocytosis · Reverse Transcriptase Polymerase Chain Reaction · RNA, Messenger · Toll-Like Receptor 8

Abstract

Activated microglia are found in a variety of neuroinflammatory disorders where they have attributed roles as effector as well as antigen-presenting cells (APC). Critical determinants for the multifaceted role of microglia are the differentiation potential of microglia and their mode of activation. In this study, we have investigated the effects of M-CSF and GM-CSF-mediated differentiation of adult primate microglia on their cellular phenotype, antigen presentation, and phagocytic function as well as on Toll-like receptor (TLR)-mediated responses. We show that although cell morphology and expression levels of activation markers were markedly different, differentiation with either factor yielded microglia that phenotypically and functionally resemble macrophages. Both M-CSF and GM-CSF-differentiated microglia were responsive to TLR1/2, 2, 3, 4, 5, 6/2, and 8-mediated activation, but not to TLR7 or 9-mediated activation. Intriguingly, M-CSF-differentiated microglia expressed higher levels of TLR8-encoding mRNA and protein, and produced larger amounts of proinflammatory cytokines in response to TLR8-mediated activation as compared to GM-CSF-differentiated microglia. While differentiation of adult microglia by growth factors that can be produced endogenously in the central nervous system is thus unlikely to change their APC function, it can alter their innate responses to infectious stimuli such as ssRNA viruses. Resident primate microglia may thereby help shape rather than initiate adaptive immune responses. © 2007 Wiley-Liss, Inc.