The CNS mononuclear phagocyte system in health and disease

Mundt, Sarah; Greter, Melanie

doi:10.1016/j.neuron.2022.10.005

Cited by 41 publications

(25 citation statements)

References 186 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although additional lineage tracing studies are needed, these findings suggest that microglia are dynamic responders to injury, while engrafted macrophages exert constant inflammatory influence on the CNS. A similar perspective has been highlighted in a recent article on the role of CNS mononuclear phagocytes in health and disease, which proposes that tissue-resident macrophages (i.e., microglia and BAMs) exert tissue-protective functions such as debris clearance and functional support, while blood-borne phagocytes are the primary drivers of neuroinflammation ( Mundt et al, 2022 ).…”

Section: Discussion and Perspectivesmentioning

confidence: 65%

Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease

Pitts

Margeta

2023

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Microglia are dynamic guardians of neural tissue and the resident immune cells of the central nervous system (CNS). The disease-associated microglial signature (DAM), also known as the microglial neurodegenerative phenotype (MGnD), has gained significant attention in recent years as a fundamental microglial response common to various neurodegenerative disease pathologies. Interestingly, this signature shares many features in common with developmental microglia, suggesting the existence of recycled gene programs which play a role both in early neural circuit formation as well as in response to aging and disease. In addition, recent advances in single cell RNA sequencing have revealed significant heterogeneity within the original DAM signature, with contributions from both yolk sac-derived microglia as well as bone marrow-derived macrophages. In this review, we examine the role of the DAM signature in retinal development and disease, highlighting crosstalk between resident microglia and infiltrating monocytes which may critically contribute to the underlying mechanisms of age-related neurodegeneration.

show abstract

Section: Discussion and Perspectivesmentioning

confidence: 65%

Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease

Pitts

Margeta

2023

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Microglial phagocytosis has been studied for its role in brain development (Cunningham et al., 2013; Matcovitch‐Natan et al., 2016; Wake et al., 2013) and maintenance of homeostasis through surveillance and cleaning of cell debris, including dead cells and abnormal protein aggregates (Li & Barres, 2018; Mundt et al., 2022; Nimmerjahn et al., 2005; Salter & Stevens, 2017; Streit et al., 2004). Drug discovery targeting microglial phagocytosis function has been proposed as a therapeutic strategy for Alzheimer's disease and other neurodegenerative diseases (Nizami et al., 2019; Salter & Stevens, 2017).…”

Section: Commentarymentioning

confidence: 99%

“…Microglia, the resident immune cells of the brain parenchyma, play critical functions to maintain homeostasis in the brain tissue environment, ensuring normal neuronal activities (Kettenmann et al., 2011; Nimmerjahn et al., 2005; Salter & Stevens, 2017; Wake et al., 2013). Cleaning debris of dead cells and extracellular abnormal protein aggregates through phagocytosis is the major homeostasis function of microglia (Edler et al., 2021; Ennerfelt et al., 2022; Franco‐Bocanegra et al., 2021; Mundt et al., 2022; Nizami et al., 2019; Witting et al., 2000). Decline of phagocytosis activity has been observed in Alzheimer's disease (AD) brains (Lewcock et al., 2020; Mundt et al., 2022), especially in plaque associated microglia (Gyoneva et al., 2016; Plescher et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Cleaning debris of dead cells and extracellular abnormal protein aggregates through phagocytosis is the major homeostasis function of microglia (Edler et al., 2021; Ennerfelt et al., 2022; Franco‐Bocanegra et al., 2021; Mundt et al., 2022; Nizami et al., 2019; Witting et al., 2000). Decline of phagocytosis activity has been observed in Alzheimer's disease (AD) brains (Lewcock et al., 2020; Mundt et al., 2022), especially in plaque associated microglia (Gyoneva et al., 2016; Plescher et al., 2018). Accumulation of Aβ plaques and Tau tangles in AD brains suggest that microglia lack the capacity to maintain homeostasis in diseased brains, and that this deficiency contributes to the neurodegenerative pathology leading to dementia.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Microglial Phagocytosis/Cell Health High‐Content Assay

2023

View full text Add to dashboard Cite

We report a microglial phagocytosis/cell health high-content assay that has been used to test small molecule chemical probes and support our drug discovery projects targeting microglia for Alzheimer's disease therapy. The assay measures phagocytosis and cell health (cell count and nuclear intensity) simultaneously in 384-well plates processed with an automatic liquid handler. The mix-and-read live cell imaging assay is highly reproducible with capacity to meet drug discovery research needs. Assay procedures take 4 days including plating cells, treating cells, adding pHrodo-myelin/membrane debris to cells for phagocytosis, staining cell nuclei before performing high-content imaging, and analysis. Three selected parameters are measured from cells: 1) mean total fluorescence intensity per cell of pHrodo-myelin/membrane debris in phagocytosis vesicles to quantify phagocytosis; 2) cell counts per well (measuring compound effects on proliferation and cell death); and 3) average nuclear intensity (measuring compound induced apoptosis). The assay has been used on HMC3 cells (an immortalized human microglial cell line), BV2 cells (an immortalized mouse microglial cell line), and primary microglia isolated from mouse brains. Simultaneous measurements of phagocytosis and cell health allow for the distinction of compound effects on regulation of phagocytosis from cellular stress/toxicity related changes, a distinguishing feature of the assay. The combination of cell counts and nuclear intensity as indicators of cell health is also an effective way to measure cell stress and compound cytotoxicity, which may have broad applications as simultaneous profiling measurements for other phenotypic assays.

show abstract

“…BAMs are located in the CNS boundary area, which is related to their special barrier function and immune regulation ( 22 ). Moreover, the CNS in a stable state has been examined immunologically ( 23 , 24 ). After infection in the CNS, the interaction between infiltrating T cells and activated microglia can maintain the function of T effector cells in CNS parenchyma ( 23 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity

Zhao

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Glioblastomas (GBMs) are highly aggressive brain tumors that have developed resistance to currently available conventional therapies, including surgery, radiation, and systemic chemotherapy. In this study, we investigated the safety of a live attenuated Japanese encephalitis vaccine strain (JEV-LAV) virus as an oncolytic virus for intracerebral injection in mice. We infected different GBM cell lines with JEV-LAV to investigate whether it had growth inhibitory effects on GBM cell lines in vitro. We used two models for evaluating the effect of JEV-LAV on GBM growth in mice. We investigated the antitumor immune mechanism of JEV-LAV through flow cytometry and immunohistochemistry. We explored the possibility of combining JEV-LAV with PD-L1 blocking therapy. This work suggested that JEV-LAV had oncolytic activity against GBM tumor cells in vitro and inhibited their growth in vivo. Mechanistically, JEV-LAV increased CD8+ T cell infiltration into tumor tissues and remodeled the immunosuppressive GBM microenvironment that is non-conducive to immunotherapy. Consequently, the results of combining JEV-LAV with immune checkpoint inhibitors indicated that JEV-LAV therapy improved the response of aPD-L1 blockade therapy against GBM. The safety of intracerebrally injected JEV-LAV in animals further supported the clinical use of JEV-LAV for GBM treatment.

show abstract

The CNS mononuclear phagocyte system in health and disease

Cited by 41 publications

References 186 publications

Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease

Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease

Microglial Phagocytosis/Cell Health High‐Content Assay

Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity

Contact Info

Product

Resources

About