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Direct and Indirect Effects of Immune and Central Nervous System−Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation This information is current as of October 1, 2021. Craig S. Moore, Qiao-Ling Cui, Nebras M. Warsi, Bryce A. Durafourt, Nika Zorko, David R. Owen, Jack P. Antel and Amit Bar-Or J Immunol 2015; 194:761-772; Prepublished online 10 December 2014; Downloaded from doi: 10.4049/jimmunol.1401156 http://www.jimmunol.org/content/194/2/761 Supplementary http://www.jimmunol.org/content/suppl/2014/12/10/jimmunol.140115 http://www.jimmunol.org/ Material 6.DCSupplemental References This article cites 60 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/194/2/761.full#ref-list-1 Why The JI? Submit online. by guest on October 1, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Direct and Indirect Effects of Immune and Central Nervous System–Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation Craig S. Moore, Qiao-Ling Cui, Nebras M. Warsi, Bryce A. Durafourt, Nika Zorko, David R. Owen,1 Jack P. Antel, and Amit Bar-Or In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti- Downloaded from inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5+ neural progenitors, resulting in decreased O4+ and GalC+ oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differ- http://www.jimmunol.org/ entiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte-lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes. The Journal of Immunology, 2015, 194: 761–772. hronic inflammation within the CNS plays a key role in including TNF-a, compared with more mature oligodendrocyte- the pathophysiology of multiple sclerosis (MS). Although lineage cells (4–7). C inflammation can result in demyelination and axonal Cellular interactions between proinflammatory immune cells and by guest on October 1, 2021 damage, it can also stimulate neuroprotection and myelin repair (1). CNS-resident cells were suggested to promote CNS tissue injury. In Given these observations, it is hypothesized that complex neuro- contrast, interactions between “anti-inflammatory” immune cells and immunological interactions between immune cells and neural cells CNS-resident cells promote tissue repair and/or neuroprotection (8). are important determinants of the net tissue effects of CNS in- Although this concept has been supported in animal models of CNS flammation (1, 2). In MS, successful remyelination in the injured inflammation and is consistent with the presumed mechanisms of CNS is dependent on the survival and differentiation of oligoden- action of several immunomodulatory disease-modifying therapies drocyte progenitor cells (OPCs) rather than process regeneration by (DMTs) used in the treatment of MS, there have been no studies mature, myelinating oligodendrocytes. Our recent in situ anal- directly assessing the contributions of human disease–relevant im- ysis of active MS lesions suggested that OPCs are more vul- mune cell subsets (including T cells, macrophages, and microglia) to nerable to injury than mature oligodendrocytes within the same the biology and fate of human OPCs. Given the limited capacity of lesion site (3). In vitro and animal studies also implicated en- OPCs to differentiate and, subsequently, remyelinate with disease hanced vulnerability of OPCs to proinflammatory mediators, duration (9), it is critical to understand the contributions of resident neural cells (including microglia and astrocytes) and peripheral- derived inflammatory immune cells in this process. Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neu- rological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada In MS, infiltrating immune cells belonging to both the adaptive 1Current address: Division of Brain Sciences, Department of Medicine, Imperial and innate immune systems can physically interact with CNS- College London, London, U.K. resident cells, but they also secrete soluble immunoregulatory Received for publication May 8, 2014. Accepted for publication November 10, 2014. and neuroregulatory factors that can influence the biology of cells Address correspondence and reprint requests to Prof. Amit Bar-Or, Montreal Neuro- residing in the CNS (1). Among the cells of the adaptive immune logical Institute, Neuroimmunology Unit, Room 111, 3801 University Street, Mon- system, T cells are thought to play a particularly prominent role in treal, QC H3A 2B4, Canada. E-mail address: [email protected] MS pathophysiology (8). In attempts to model the contributions of The online version of this article contains supplemental material. these cells in vitro, T cells can be polarized into three distinct Abbreviations used in this article: ACM, astrocyte-conditioned media; DMT, disease- modifying therapy; IHC, immunohistochemistry; MDM, monocyte-derived macro- subsets: Th1, Th17, and Th2. In the context of MS, Th1- and Th17- phage; MS, multiple sclerosis; OPC, oligodendrocyte progenitor cell; SCI, spinal polarized T cells are considered proinflammatory, while promoting cord injury. damage and demyelination in the CNS. Conversely, Th2-polarized Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 immune cells are generally considered anti-inflammatory and are www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401156 762 IMMUNE CELL REGULATION OF OLIGODENDROCYTE DIFFERENTIATION believed to protect the CNS from damaging inflammation and #50,000 pg/ml IFN-g, which was significantly less than in Th1-polarized potentially promote repair (8). supernatants. Supernatants of PBMCs that were activated, but not polarized, were used as controls. In the CNS, innate immune cells belonging to the myeloid Polarized myeloid cell supernatants were generated using previously pub- lineage, including blood-derived macrophages and CNS-resident lished protocols (19). Comprehensive characterization of the phenotype and microglia, also can play a significant role in the pathophysiology functional properties of our polarized human macrophages and microglia was + of MS. Similar to T cells, myeloid cells can be polarized into performed previously (11, 12, 19). Briefly, CD14 monocytes were positively selected from PBMCs using anti-CD14 MicroBeads (Miltenyi Biotec, proinflammatory M1 (classical activation) and anti-inflammatory 5 Auburn, CA). Cells were then plated at a density of 5 3 10 cells/ml in RPMI M2 (alternative activation) phenotypes (10–12). We showed pre- 1640 containing 10% FCS, penicillin/streptomycin, and glutamine. For M1 viously that exposure of human microglia to Th1 supernatants can polarization, monocytes were treated with rGM-CSF (5 ng/ml) and cul- induce an M1-like phenotype (13, 14). Although M1 macrophages tured for 5 d. Cells were then activated with IFN-g (20 ng/ml) for 1 h, and microglia secrete proinflammatory cytokines and are pre- followed by LPS (100 ng/ml) for 48 h. For M2 polarization, cells were treated with M-CSF (25 ng/ml) for 5 d, followed by stimulation with IL-4 dominant in active MS lesions, phagocytic myelin-laden macro- (20 ng/ml) and IL-13 (20 ng/ml) for 48 h. Human adult microglia were phages
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