Microglia versus Monocytes: Distinct Roles in Degenerative Diseases of the Retina

Yu, Chen; Roubeix, Christophe; Sennlaub, Florian; Saban, Daniel R.

doi:10.1016/j.tins.2020.03.012

Cited by 105 publications

(116 citation statements)

References 131 publications

(233 reference statements)

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“…Of particular relevance here is the increased expression of degradative lysosomal enzymes such as dipeptidyl peptidase, tripeptidyl peptidase, and Cathepsin D (CatD) in microglial cells as compared to macrophages (Majumdar et al, 2007 ). Also important in this regard are differences between microglial cells from inflamed CNS and those recruited from blood-derived monocytes; the substantial differences recently identified between these cell types implies their response to the P2X 7 receptor could well differ (Lapenna et al, 2018 ; Borst and Prinz, 2020 ; Yu et al, 2020 ). While the relative paucity of data from microglial cells on how the P2X 7 receptor alters clearance means that some of the information presented in this review has been obtained from macrophages, the reader should be aware that application of results from macrophages to microglial cells has limitations.…”

Section: Microglia Inflammation and Clearancementioning

confidence: 99%

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

Campagno

Mitchell

2021

Front. Cell. Neurosci.

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Microglial cells regulate neural homeostasis by coordinating both immune responses and clearance of debris, and the P2X7 receptor for extracellular ATP plays a central role in both functions. The P2X7 receptor is primarily known in microglial cells for its immune signaling and NLRP3 inflammasome activation. However, the receptor also affects the clearance of extracellular and intracellular debris through modifications of lysosomal function, phagocytosis, and autophagy. In the absence of an agonist, the P2X7 receptor acts as a scavenger receptor to phagocytose material. Transient receptor stimulation induces autophagy and increases LC3-II levels, likely through calcium-dependent phosphorylation of AMPK, and activates microglia to an M1 or mixed M1/M2 state. We show an increased expression of Nos2 and Tnfa and a decreased expression of Chil3 (YM1) from primary cultures of brain microglia exposed to high levels of ATP. Sustained stimulation can reduce lysosomal function in microglia by increasing lysosomal pH and slowing autophagosome-lysosome fusion. P2X7 receptor stimulation can also cause lysosomal leakage, and the subsequent rise in cytoplasmic cathepsin B activates the NLRP3 inflammasome leading to caspase-1 cleavage and IL-1β maturation and release. Support for P2X7 receptor activation of the inflammasome following lysosomal leakage comes from data on primary microglia showing IL-1β release following receptor stimulation is inhibited by cathepsin B blocker CA-074. This pathway bridges endolysosomal and inflammatory roles and may provide a key mechanism for the increased inflammation found in age-dependent neurodegenerations characterized by excessive lysosomal accumulations. Regardless of whether the inflammasome is activated via this lysosomal leakage or the better-known K+-efflux pathway, the inflammatory impact of P2X7 receptor stimulation is balanced between the autophagic reduction of inflammasome components and their increase following P2X7-mediated priming. In summary, the P2X7 receptor modulates clearance of extracellular debris by microglial cells and mediates lysosomal damage that can activate the NLRP3 inflammasome. A better understanding of how the P2X7 receptor alters phagocytosis, lysosomal health, inflammation, and autophagy can lead to therapies that balance the inflammatory and clearance roles of microglial cells.

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Section: Microglia Inflammation and Clearancementioning

confidence: 99%

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

Campagno

Mitchell

2021

Front. Cell. Neurosci.

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“…We observed strong immunolabeling for caspase-1 or its activation product p10 predominantly in F4/80 + cells in CNV lesions of Vegfa hyper mice, whereas no strong immunolabeling was detected in their RPE cells ( Figure 3A–C ). In the eye, both macrophages as well as retinal microglia express F4/80 ( Yu et al, 2020 ). Notably, we observed that a subset of F4/80 + cells that infiltrate CNV lesions in Vegfa hyper mice and showed caspase-1 p10 labeling also expressed the microglia marker P2RY12, whereas P2RY12 + microglia in the retina at sites devoid of CNV lesions did not label for caspase-1 p10 ( Figure 3C ; Figure 3—figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization

Malsy

Alvarado

Lamontagne

et al. 2020

eLife

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NLRP3 inflammasome activation and complement-mediated inflammation have been implicated in promoting choroidal neovascularization (CNV) in age-related macular degeneration (AMD), but central questions regarding their contributions to AMD pathogenesis remain unanswered. Key open questions are (1) whether NLRP3 inflammasome activation mainly in retinal pigment epithelium (RPE) or rather in non-RPE cells promotes CNV, (2) whether inflammasome activation in CNV occurs via NLRP3 or also through NLRP3-independent mechanisms, and (3) whether complement activation induces inflammasome activation in CNV. Here we show in a neovascular AMD mouse model that NLRP3 inflammasome activation in non-RPE cells but not in RPE cells promotes CNV. We demonstrate that both NLRP3-dependent and NLRP3-independent inflammasome activation mechanisms induce CNV. Finally, we find that complement and inflammasomes promote CNV through independent mechanisms. Our findings uncover an unexpected role of non-NLRP3 inflammasomes for CNV and suggest that combination therapies targeting inflammasomes and complement may offer synergistic benefits to inhibit CNV.

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“…47 In addition, activation patterns and implications in the curse of the disease, that is, neurodegenerative disorders. 14,15 Lastly, because specific microglial genes are expressed by the STR-MP, the STR-MP can potentially be used as a tool for developing diagnostic approaches and in the search for bio-…”

Section: Str-m In a Human Ex Vivo Brain Modelmentioning

confidence: 99%

The human bone marrow harbors a CD45− CD11B+ cell progenitor permitting rapid microglia-like cell derivative approaches

Bruzelius

Hidalgo

Boza-Serrano

et al. 2020

Stem Cells Translational Medicine

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Microglia, the immune sentinel of the central nervous system (CNS), are generated from yolk sac erythromyeloid progenitors that populate the developing CNS. Interestingly, a specific type of bone marrow-derived monocyte is able to express a yolk sac microglial signature and populate CNS in disease. Here we have examined human bone marrow (hBM) in an attempt to identify novel cell sources for generating microglia-like cells to use in cell-based therapies and in vitro modeling. We demonstrate that hBM stroma harbors a progenitor cell that we name stromal microglial progenitor (STR-MP). STR-MP single-cell gene analysis revealed the expression of the consensus genetic microglial signature and microglial-specific genes present in development and CNS pathologies. STR-MPs can be expanded and generate microglia-like cells in vitro, which we name stromal microglia (STR-M). STR-M cells show phagocytic ability, classically activate, and survive and phagocyte in human brain tissue. Thus, our results reveal that hBM harbors a source of microglia-like precursors that can be used in patient-centered fast derivative approaches. K E Y W O R D S bone marrow, common myeloid progenitor, human bone marrow, microglia, microglial precursor, microglia-like cell in vitro model, primitive myeloid progenitor, pluripotent stem cell 1 | INTRODUCTION Microglia are generated from yolk sac erythromyeloid progenitors (EMPs) that populate the developing central nervous system (CNS) to become its resident macrophage. 1,2 Microglia play a key role in the brain development, ensure maintenance and function during adulthood, 3 and are involved in the onset and progression of CNS pathologies, including neurodegenerative and psychiatric disorders 4 as well as malignant brain tumors. 5 Microglia constitute a target for therapy. 6 Development of drugs tries to target microglia for Johan Bengzon and Tania Ramos-Moreno contributed equally as senior authors.

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Microglia versus Monocytes: Distinct Roles in Degenerative Diseases of the Retina

Cited by 105 publications

References 131 publications

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization

The human bone marrow harbors a CD45− CD11B+ cell progenitor permitting rapid microglia-like cell derivative approaches

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