A new genetic strategy for targeting microglia in development and disease

McKinsey, Gabriel L.; Lizama, Carlos O; Keown-Lang, Amber E; Niu, Abraham; Santander, Nicolás; Larpthaveesarp, Amara; Chee, Elin; Gonzalez, Fernando; Arnold, Thomas D.

doi:10.7554/elife.54590

Cited by 129 publications

(134 citation statements)

References 59 publications

(100 reference statements)

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“…Due to difficulties distinguishing microglia from monocyte-derived macrophages within the lesion, no studies to date have been able to assign intralesional functional differences between these two cell populations with ageing. The advent of phenotypic markers and genetic fate-mapping strategies to distinguish these two populations opens up a promising new avenue of inquiry ( 110 , 154 , 155 ). Circumstantially, it has been documented that the ageing process manifests differently in microglia compared to monocyte-derived macrophages.…”

Section: Age-associated Remyelination Decline Involves Impaired Micromentioning

confidence: 99%

Microglia Diversity in Health and Multiple Sclerosis

et al. 2020

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Multiple Sclerosis (MS) is a neurodegenerative disease characterized by multiple focal lesions, ongoing demyelination and, for most people, a lack of remyelination. MS lesions are enriched with monocyte-derived macrophages and brain-resident microglia that, together, are likely responsible for much of the immune-mediated neurotoxicity. However, microglia and macrophage also have documented neuroprotective and regenerative roles, suggesting a potential diversity in their functions. Linked with microglial functional diversity, they take on diverse phenotypes developmentally, regionally and across disease conditions. Advances in technologies such as single-cell RNA sequencing and mass cytometry of immune cells has led to dramatic developments in understanding the phenotypic changes of microglia and macrophages. This review highlights the origins of microglia, their heterogeneity throughout normal ageing and their contribution to pathology and repair, with a specific focus on autoimmunity and MS. As phenotype dictates function, the emerging heterogeneity of microglia and macrophage populations in MS offers new insights into the potential immune mechanisms that result in inflammation and regeneration.

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Section: Age-associated Remyelination Decline Involves Impaired Micromentioning

confidence: 99%

Microglia Diversity in Health and Multiple Sclerosis

et al. 2020

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“…In this context signature genes of microglia of the homoeostatic brain were identified, including Tmem119 , Sall1 , P2ry12 , Olfml3 , Hexb , Fcrls , Siglech , Tgfbr1, and Gpr34 [ 60 , 105 , 108 , 109 , 110 , 111 , 112 ]. A part of these genes was used to develop new reporter mice to label and/or genetically manipulate the microglia cell population [ 113 ]: Tmem119 eGFP and Tmem119 CreERT2 [ 114 ], Tmem119 TdTomato [ 115 ], Sall1 GFP , and Sall1 CreER [ 116 , 117 ], and Hexb TdTomato and Hexb CreERT2 [ 118 ], and P2ry12 CreER [ 119 ].…”

Section: Distinction Of Microglia and Macrophages In Gliomamentioning

confidence: 99%

“…Thus, microglia were not compared to brain-infiltrated macrophages therefore limiting the statement about marker specificity. Notably, several of these microglia genes such as Tmem119 , Sall1, and P2ry12 could be downregulated in different brain pathologies [ 120 , 121 , 122 ] and are not completely restricted to the microglia cell population [ 118 , 119 , 123 , 124 ], which could additionally impede a distinct discrimination of microglia and macrophages in the diseased brain. Hexb showed the most stable expression also in the diseased brain (e.g., neurodegeneration), implicating that the Hexb TdTomato reporter mice [ 118 ] should be considered for investigation of the myeloid cell composition of CNS tumors.…”

Section: Distinction Of Microglia and Macrophages In Gliomamentioning

confidence: 99%

Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks?

Brandenburg

Blank

Bungert

et al. 2020

IJMS

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For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.

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“…However, one needs to keep in mind, that this model also labels CAM, some tissue macrophages in the periphery as well as monocytes until they are replaced by new ones from the BM (4 weeks) (48). Because of these shortcomings, an array of new mouse lines have been established in order to target microglia in the CNS by using seemingly microglia-specific Cre-drivers (SALL1, P2RY12, TMEM119, and HEXB) (20,77,115,120). The targeting specificity of these mouse lines has been nicely compiled in two recent reviews (8,131).…”

Section: Experimental Models For Msmentioning

confidence: 99%

“…While mouse models which potentially target CAM but not microglia have been developed, most of them show high off-target recombination in cells other than microglia. These include PF4-Cre, MRC1-Cre-ERT2, LYVE1-Cre, and CD169-Cre mice (80,120,136,147,149,181). To perform detailed fate-mapping studies Cre-ERT2 mice are of advantage for pulse labeling, whereas for gene deletion studies a preferably cell type-specific marker with little off-target deletion is needed.…”

Section: Experimental Models For Msmentioning

confidence: 99%

Deciphering the heterogeneity of myeloid cells during neuroinflammation in the single‐cell era

Borst

Prinz

2020

Brain Pathology

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Multiple sclerosis (MS) is a disabling neuroinflammatory disease, which is little understood and lacks a sufficient therapeutic regimen. Myeloid cells have repeatedly shown to play a pivotal role in the disease progression. During homeostasis, only the CNS‐resident microglia and CNS‐associated macrophages are present in the CNS. Neuroinflammation causes peripheral immune cells to infiltrate the CNS contributing to disease progression and neurological sequelae. The differential involvement of the diverse peripheral and resident myeloid cell subsets to the disease pathogenesis and outcome are highly debated and difficult to assess. However, novel technological advances (new mouse models, single‐cell RNA‐Sequencing, and CYTOF) have improved the depth of immune profiling, which allows the characterization of distinct myeloid subsets. This review provides an overview of current knowledge on the phenotypes and roles of these different myeloid subsets in neuroinflammatory disease and their therapeutic relevance.

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A new genetic strategy for targeting microglia in development and disease

Cited by 129 publications

References 59 publications

Microglia Diversity in Health and Multiple Sclerosis

Microglia Diversity in Health and Multiple Sclerosis

Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks?

Deciphering the heterogeneity of myeloid cells during neuroinflammation in the single‐cell era

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