Microglia of the Brain: Origin, Structure, Functions

Alekseeva, O. S.; Кирик, О. В.; Gilerovich, E. G.; Коржевский, Д. Э.

doi:10.1134/s002209301904001x

Cited by 14 publications

(7 citation statements)

References 68 publications

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“…In vivo investigation of these cells has been substantively aided by the small molecule inhibitor of CSF-1R tyrosine kinase activity, PLX5622, typically formulated into a standard rodent chow to enable oral administration. This drug readily penetrates the blood brain barrier (BBB) and can deplete > 90% of microglia in as little as three days (31)(32)(33). Removal of PLX5622 causes rapid microglia replenishment via the proliferation of surviving microglia (34).…”

Section: Introductionmentioning

confidence: 99%

PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production

Spiteri

Ling

et al. 2022

Front. Immunol.

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PLX5622 is a CSF-1R inhibitor and microglia-depleting reagent, widely used to investigate the biology of this central nervous system (CNS)-resident myeloid population, but the indirect or off-target effects of this agent remain largely unexplored. In a murine model of severe neuroinflammation induced by West Nile virus encephalitis (WNE), we showed PLX5622 efficiently depleted both microglia and a sub-population of border-associated macrophages in the CNS. However, PLX5622 also significantly depleted mature Ly6Chi monocytes in the bone marrow (BM), inhibiting their proliferation and lethal recruitment into the infected brain, reducing neuroinflammation and clinical disease scores. Notably, in addition, BM dendritic cell subsets, plasmacytoid DC and classical DC, were depleted differentially in infected and uninfected mice. Confirming its protective effect in WNE, cessation of PLX5622 treatment exacerbated disease scores and was associated with robust repopulation of microglia, rebound BM monopoiesis and markedly increased inflammatory monocyte infiltration into the CNS. Monoclonal anti-CSF-1R antibody blockade late in WNE also impeded BM monocyte proliferation and recruitment to the brain, suggesting that the protective effect of PLX5622 is via the inhibition of CSF-1R, rather than other kinase targets. Importantly, BrdU incorporation in PLX5622-treated mice, suggest remaining microglia proliferate independently of CSF-1 in WNE. Our study uncovers significantly broader effects of PLX5622 on the myeloid lineage beyond microglia depletion, advising caution in the interpretation of PLX5622 data as microglia-specific. However, this work also strikingly demonstrates the unexpected therapeutic potential of this molecule in CNS viral infection, as well as other monocyte-mediated diseases.

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Section: Introductionmentioning

confidence: 99%

PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production

Spiteri

Ling

et al. 2022

Front. Immunol.

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“…Microglia deliver immune protection for the posterior eye, including the neural retina, and have an involvement with some sight-threatening conditions, such as age-related macular degeneration, uveitis, glaucoma, and retinal degeneration ( Rashid et al., 2019 ). Despite the key role of microglia in facilitating our immune defenses, their developmental origin has attracted controversy, and the question remains unresolved as to whether they emerge from the ectoderm or the mesoderm ( Alekseeva et al., 2019 ; Ginhoux and Prinz, 2015 ). It is also uncertain whether or not microglia can form in isolation from the vasculature in tissues such as the eye.…”

Section: Introductionmentioning

confidence: 99%

PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids

et al. 2022

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Summary Microglia are the resident immune cells of the central nervous system (CNS). They govern the immunogenicity of the retina, which is considered to be part of the CNS; however, it is not known how microglia develop in the eye. Here, we studied human-induced pluripotent stem cells (hiPSCs) that had been expanded into a self-formed ectodermal autonomous multi-zone (SEAM) of cells that partially mimics human eye development. Our results indicated that microglia-like cells, which have characteristics of yolk-sac-like linage cells, naturally develop in 2D eye-like SEAM organoids, which lack any vascular components. These cells are unique in that they are paired box protein 6 (PAX6)-positive, yet they possess some characteristics of mesoderm. Collectively, the data support the notion of the existence of an isolated, locally developing immune system in the eye, which is independent of the body’s vasculature and general immune system.

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“…Since their discovery, different theories were developed about their origin. Pio del Rio-Hortega firstly introduced the hypothesis of a microglial mesodermal origin [12,13]. A widely supported theory suggests that microglial precursors (embryonic macrophages) originate from the yolk sac mesoderm during embryogenesis [12]; however, another hypothesis places microglial origin on the differentiation of microglyocytes from blood monocytes [14,15], with the latter theory originating from del Rio-Hortega, who suggested blood monocytes invade the CNS in prenatal stages [15].…”

Section: Microglia and Their Role In The Pathogenesis Of Alzheimer's ...mentioning

confidence: 99%

Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer’s Disease Pathogenesis?

Bruno

Karagil

Mahmood

et al. 2021

Cells

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The activation of microglia, the inflammatory cells of the central nervous system (CNS), has been linked to the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases. How microglia sense the changing brain environment, in order to respond appropriately, is still being elucidated. Microglia are able to sense and respond to the mechanical properties of their microenvironment, and the physical and molecular pathways underlying this mechanosensing/mechanotransduction in microglia have recently been investigated. The Hippo pathway functions through mechanosensing and subsequent protein kinase cascades, and is critical for neuronal development and many other cellular processes. In this review, we examine evidence for the potential involvement of Hippo pathway components specifically in microglia in the pathogenesis of Alzheimer’s disease. We suggest that the Hippo pathway is worth investigating as a mechanosensing pathway in microglia, and could be one potential therapeutic target pathway for preventing microglial-induced neurodegeneration in AD.

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Microglia of the Brain: Origin, Structure, Functions

Cited by 14 publications

References 68 publications

PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production

PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production

PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids

Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer’s Disease Pathogenesis?

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