Microglial Phenotypes and Functions in Multiple Sclerosis

O’Loughlin, Elaine; Madore, Charlotte; Lassmann, Hans; Butovsky, Oleg

doi:10.1101/cshperspect.a028993

Cited by 81 publications

(58 citation statements)

References 182 publications

(215 reference statements)

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“…Although the core signature of homeostatic microglia is basically preserved in the entire CNS, there are differences in the expression patterns of homeostatic genes during different stages of fetal development and in different CNS regions in the adult brain (Grabert et al, 2016;Michell-Robinson et al, 2015;O'Loughlin, Madore, Lassmann, & Butovsky, 2018). This allows the differentiation of heterogeneous microglia subpopulations by single cell analysis, although these different cell phenotypes rather represent a transcriptional continuum instead of distinct cellular subtypes (Masuda et al, 2019).…”

Section: Microglia In the Normal Rodent And Human Brainmentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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Section: Microglia In the Normal Rodent And Human Brainmentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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“…Under physiological conditions, phagocytic and secretory activity of these glia support neurogenesis, development of neuronal connectivity, and survival of neurons (Stevens et al, 2007; Sierra et al, 2010; Paolicelli et al, 2011; Schafer et al, 2012; Ueno et al, 2013; Weinhard et al, 2018). Complementing these homeostatic functions, microglia react to perturbations, which has been shown in the context of vascular injury, multiple sclerosis lesions, and neurodegeneration (Itagaki et al, 1989; Davalos et al, 2005; Ransohoff, 2016; Aguzzi and Zhu, 2017; Keren-Shaul et al, 2017; Mathys et al, 2017; O’Loughlin et al, 2018). In the future, many of these processes and their potential for therapeutic targeting will be further examined, and understanding of both homeostatic and disease-related contributions of microglia will critically depend on means to specifically identify and control them.…”

Section: Introductionmentioning

confidence: 99%

Tmem119-EGFP and Tmem119-CreERT2 transgenic mice for labeling and manipulating microglia

Kaiser

Feng

2019

Preprint

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“…MPs are a highly plastic population of different, though closely related cell types, which often convert into each other depending on the local milieu and activation status in particular in MS . Currently we cannot yet pinpoint the precise subtype of MPs that interacts with CD8 + T cells in the MS lesions; however, we assume that CD8 + T cell may communicate with several subtypes because we found them in contact with CD163 + CD11b + and CD163 − CD11b + cells.…”

Section: Discussionmentioning

confidence: 84%

“…Furthermore, many brain‐resident cells are of the mononuclear phagocyte (MP) lineage, which contains many subtypes of high plasticity (e.g., macrophages, microglia, monocytes). These cells may switch their phenotype rapidly in situ depending on changes of the local environment …”

Section: Introductionmentioning

confidence: 99%

Communication of CD8⁺ T cells with mononuclear phagocytes in multiple sclerosis

Sabolek

Held

Beltrán

et al. 2019

Ann Clin Transl Neurol

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Objective CD8+ T cells are the most prevailing lymphocyte population in inflammatory lesions of patients with multiple sclerosis (MS) but it is not even known whether they are merely passive bystanders or actively communicate with other cells in the brain. To identify their potential interaction partners, we analyzed CD8+ T cells that contained vectorially oriented cytotoxic granules and analyzed the areas to which the granules pointed. Methods We stained cryo‐sections of active MS lesions of an index patient with antibodies to CD8 and perforin, searched for vectorially oriented perforin granules, and isolated target areas opposing the granules and control areas by laser‐microdissection. From both areas, we analyzed cell‐type specific transcripts by next‐generation sequencing. In parallel, we stained samples from the index‐patient and other patients by four‐color immunohistochemistry (IHC). Results We found transcripts of the mononuclear phagocyte (MP) specific markers CD163 and CD11b only in the microdissected target areas but not in control areas. We validated the finding that MPs are communication partners of CD8+ T cells in MS lesions by classical IHC in samples from the index‐patient and other patients with acute and progressive MS and other inflammatory neurological diseases. Interpretation Because CD163 and CD11b are specifically expressed in MPs, our findings suggest that CD8+ T cells communicate with local MPs. Although it is still unclear if these interactions lead to killing of the communication partners by CD8+ T cells, our data underline that CD8+ T cells play an active role in the pathogenesis of MS.

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Microglial Phenotypes and Functions in Multiple Sclerosis

Cited by 81 publications

References 182 publications

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Tmem119-EGFP and Tmem119-CreERT2 transgenic mice for labeling and manipulating microglia

Communication of CD8⁺ T cells with mononuclear phagocytes in multiple sclerosis

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Microglial Phenotypes and Functions in Multiple Sclerosis

Cited by 81 publications

References 182 publications

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Tmem119-EGFP and Tmem119-CreERT2 transgenic mice for labeling and manipulating microglia

Communication of CD8+ T cells with mononuclear phagocytes in multiple sclerosis

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Resources

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Communication of CD8⁺ T cells with mononuclear phagocytes in multiple sclerosis