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Start Over Author "James WS" Journal frontiers in immunology
3 results on '"James WS"'

1. Type I interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia

Author

Hanrath, AT, Hatton, CF, Gothe, F, Browne, C, Vowles, J, Leary, P, Cockell, SJ, Cowley, SA, James, WS, Hambleton, S, and Duncan, CJA

Subjects
Immunology, Immunology and Allergy
Abstract

Macrophages are key target cells of Zika virus (ZIKV) infection, implicated as a viral reservoir seeding sanctuary sites such as the central nervous system and testes. This rests on the apparent ability of macrophages to sustain ZIKV replication without experiencing cytopathic effects. ZIKV infection of macrophages triggers an innate immune response involving type I interferons (IFN-I), key antiviral cytokines that play a complex role in ZIKV pathogenesis in animal models. To investigate the functional role of the IFN-I response we generated human induced pluripotent stem cell (iPSC)-derived macrophages from a patient with complete deficiency of IFNAR2, the high affinity IFN-I receptor subunit. Accompanying the profound defect of IFN-I signalling in IFNAR2 deficient iPS-macrophages we observed significantly enhanced ZIKV replication and cell death, revealing the inherent cytopathicity of ZIKV towards macrophages. These observations were recapitulated by genetic and pharmacological ablation of IFN-I signalling in control iPS-macrophages and extended to a model of iPS-microglia. Thus, the capacity of macrophages to support noncytolytic ZIKV replication depends on an equilibrium set by IFN-I, suggesting that innate antiviral responses might counterintuitively promote ZIKV persistence via the maintenance of tissue viral reservoirs relevant to pathogenesis.

Published
2022
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2. Density dependent regulation of inflammatory responses in macrophages.

Author

Vaughan-Jackson A, Stodolak S, Ebrahimi KH, Johnson E, Reardon PK, Dupont M, Zhang S, McCullagh JSO, and James WS

Subjects
Humans, Cell Differentiation, Macrophages metabolism, Monocytes metabolism, Cytokines metabolism, Induced Pluripotent Stem Cells metabolism
Abstract

Macrophage distribution density is tightly regulated within the body, yet the importance of macrophage crowding during in vitro culture is largely unstudied. Using a human induced pluripotent stem cell (iPSC)-derived macrophage model of tissue resident macrophages, we characterize how increasing macrophage culture density changes their morphology and phenotype before and after inflammatory stimulation. In particular, density drives changes in macrophage inflammatory cytokine and chemokine secretion in both resting and activated states. This density regulated inflammatory state is also evident in blood monocyte derived-macrophages, the human monocytic THP-1 immortalized cell line, and iPSC-derived microglia. Density-dependent changes appear to be driven by a transferable soluble factor, yet the precise mechanism remains unknown. Our findings highlight cell plating density as an important but frequently overlooked consideration of in vitro macrophage research relevant to a variety of fields ranging from basic macrophage cell biology to disease studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vaughan-Jackson, Stodolak, Ebrahimi, Johnson, Reardon, Dupont, Zhang, McCullagh and James.)

Published
2022
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3. Honing the Double-Edged Sword: Improving Human iPSC-Microglia Models.

Author

Hedegaard A, Stodolak S, James WS, and Cowley SA

Subjects
Animals, Cells, Cultured, Coculture Techniques, Culture Media pharmacology, Culture Media, Serum-Free pharmacology, Heterografts, Humans, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells transplantation, Inflammation immunology, Mice, Microglia drug effects, Neurodegenerative Diseases immunology, Neurodegenerative Diseases pathology, Cell Culture Techniques, Cellular Microenvironment, Induced Pluripotent Stem Cells cytology, Microglia cytology, Models, Biological
Abstract

Human induced Pluripotent Stem Cell (hiPSC) models are a valuable new tool for research into neurodegenerative diseases. Neuroinflammation is now recognized as a key process in neurodegenerative disease and aging, and microglia are central players in this. A plethora of hiPSC-derived microglial models have been published recently to explore neuroinflammation, ranging from monoculture through to xenotransplantation. However, combining physiological relevance, reproducibility, and scalability into one model is still a challenge. We examine key features of the in vitro microglial environment, especially media composition, extracellular matrix, and co-culture, to identify areas for improvement in current hiPSC-microglia models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Hedegaard, Stodolak, James and Cowley.)

Published
2020
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