Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis

Böttcher, Chotima; Poel, Marlijn van der; Fernández-Zapata, Camila; Schlickeiser, Stephan; Leman, Julia Koehler; Hsiao, Cheng-Chih; Mizee, Mark R.; Adelia,; Vincenten, Maria C. J.; Kunkel, Désirée; Huitinga, Inge; Hamann, Jörg; Priller, Josef

doi:10.1186/s40478-020-01010-8

Cited by 41 publications

(36 citation statements)

References 67 publications

(134 reference statements)

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“…In biopsies of active lesions in early cases of MS, diseasesassociated microglia subsets showed the expected general downregulation of GPCR genes associated with microglia homeostasis. Single-cell mass cytometry indeed confirmed the appearance of active MS lesion-enriched clusters with a downregulated surface expression of P2Y 12 , CX3CR1, and GPR56 (31).…”

Section: Discussionmentioning

confidence: 69%

GPCRomics of Homeostatic and Disease-Associated Human Microglia

et al. 2021

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G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes CX3CR1, GPR34, GPR183, P2RY12, P2RY13, and ADGRG1. Expression of these microglial core genes was lost upon culture of isolated cells ex vivo but could be acquired by human induced pluripotent stem cell (iPSC)-derived microglial precursors transplanted into mouse brains. CXCR4 and PTGER4 were higher expressed in subcortical white matter compared to cortical grey matter microglia, and ADGRG1 was downregulated in microglia obtained from normal-appearing white and grey matter tissue of multiple sclerosis (MS) brains. Single-cell RNA sequencing of microglia from active lesions, obtained early during MS, revealed downregulation of homeostasis-associated GPCR genes and upregulation of CXCR4 expression in a small subset of MS-associated lesional microglia. Functional presence of low levels of CXCR4 on human microglia was confirmed using flow cytometry and transwell migration towards SDF-1. Microglia abundantly expressed the GPCR down-stream signaling mediator genes GNAI2 (αi2), GNAS (αs), and GNA13 (α13), the latter particularly in white matter. Drugs against several microglia GPCRs are available to target microglia in brain diseases. In conclusion, transcriptome profiling allowed us to identify expression of GPCRs that may contribute to brain (patho)physiology and have diagnostic and therapeutic potential in human microglia.

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Section: Discussionmentioning

confidence: 69%

GPCRomics of Homeostatic and Disease-Associated Human Microglia

et al. 2021

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“…Using single-cell mass cytometry analysis, the phenotype of activated microglia in patients with progressive MS was determined. The study revealed that highly phagocytic and activated microglia downregulated the expression of homeostatic markers such as P2Y12 and GPR56 and upregulated the expression of proteins involved in phagocytic activity and microglial activation including CD68, CCR2, CD64, CD32, CD95, and CCL4 [ 38 ]. Besides the physical presence of microglia at sites of demyelination and an upregulation of various markers, the pathophysiological function of microglia in progression is largely unclear.…”

Section: Mechanism Of Disease Progression In Msmentioning

confidence: 99%

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Geladaris

Häusler

Weber

2021

IJMS

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Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.

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“…Within the CNS parenchyma, resident and invading macrophages play complex roles both preclinically and in established lesions ( 71 ). Monocyte invasion might, however, vary at different disease stages, with less MdM infiltrates observed in progressive MS compared to RRMS ( 200 ).…”

Section: Myeloid Dwellers and Trespassers At Cns Interfaces Upon Automentioning

confidence: 99%

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System

et al. 2021

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The central nervous system (CNS) parenchyma is enclosed and protected by a multilayered system of cellular and acellular barriers, functionally separating glia and neurons from peripheral circulation and blood-borne immune cells. Populating these borders as dynamic observers, CNS-resident macrophages contribute to organ homeostasis. Upon autoimmune, traumatic or neurodegenerative inflammation, these phagocytes start playing additional roles as immune regulators contributing to disease evolution. At the same time, pathological CNS conditions drive the migration and recruitment of blood-borne monocyte-derived cells across distinct local gateways. This invasion process drastically increases border complexity and can lead to parenchymal infiltration of blood-borne phagocytes playing a direct role both in damage and in tissue repair. While recent studies and technical advancements have highlighted the extreme heterogeneity of these resident and CNS-invading cells, both the compartment-specific mechanism of invasion and the functional specification of intruding and resident cells remain unclear. This review illustrates the complexity of mononuclear phagocytes at CNS interfaces, indicating how further studies of CNS border dynamics are crucially needed to shed light on local and systemic regulation of CNS functions and dysfunctions.

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Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis

Cited by 41 publications

References 67 publications

GPCRomics of Homeostatic and Disease-Associated Human Microglia

GPCRomics of Homeostatic and Disease-Associated Human Microglia

Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System

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