Vessel-Associated Immune Cells in Cerebrovascular Diseases: From Perivascular Macrophages to Vessel-Associated Microglia

Koizumi, Takashi; Kerkhofs, Danielle; Mizuno, Toshiki; Steinbusch, Harry W.M.; Foulquier, Sébastien

doi:10.3389/fnins.2019.01291

Cited by 68 publications

(67 citation statements)

References 65 publications

(64 reference statements)

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“…The resident immune system of the CNS, namely the microglia, are established contributors to CNS malignancies ( 146 ), but there are several other phagocytic myeloid cell populations in the CNS that are also, if not more so, implicated in a poor prognosis of the most aggressive form of CNS malignancy, glioblastoma multiforme (GBM). Perivascular, meningeal, and choroid plexus macrophages of the CNS have generally been overlooked as contributors to GBM ( 147 , 148 ), but the involvement of bone marrow-derived myeloid cells has recently been established, and even positively correlated, to poor outcomes in GBM models ( 116 , 149 ). As seen in the previous cancer studies, GBM TAMs co-express M1- and M2-associated markers, again making simple surface phenotyping of cells rather difficult, and creating the need for mechanism and pathway analysis ( 116 ).…”

Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 99%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.

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Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 99%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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“…Reports from recently published studies point toward a microglial role in the formation of the blood–brain barrier and maintenance of blood vessels (Dudvarski Stankovic et al., 2016; Halder and Milner, 2019; Koizumi et al., 2019). In this context, the decline of vascular integrity and microvascular density (Xu et al., 2017) accompanied by elevated permeability of blood–brain barrier seen over the course of aging and during pathological conditions such as chronic inflammation (da Fonseca et al., 2014; Haruwaka et al., 2019) hints toward a possible vascular-related role for the DM.…”

Section: Discovering the Dark Microgliamentioning

confidence: 99%

Shedding Light on the Dark Side of the Microglia

et al. 2020

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Microglia, the resident immune cells of the central nervous system, are not a homogeneous population; their morphology, molecular profile, and even their ultrastructure greatly vary from one cell to another. Recent advances in the field of neuroimmunology have helped to demystify the enigma that currently surrounds microglial heterogeneity. Indeed, numerous microglial subtypes have been discovered such as the disease-associated microglia, neurodegenerative phenotype, and Cd11c-positive developmental population. Another subtype is the dark microglia (DM), a population defined by its ultrastructural changes associated with cellular stress. Since their first characterization using transmission electron microscopy, they have been identified in numerous disease conditions, from mouse models of Alzheimer’s disease, schizophrenia, fractalkine signaling deficiency to chronic stress, just to name a few. A recent study also identified the presence of cells with a similar ultrastructure to the DM in postmortem brain samples from schizophrenic patients, underlining the importance of understanding the function of these cells. In this minireview, we aim to summarize the current knowledge on the DM, from their initial ultrastructural characterization to their documentation in various pathological contexts across multiple species. We will also highlight the current limitations surrounding the study of these cells and the future that awaits the DM.

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“…We expected therefore that the PLX5622 treatment would lead to a mild reduction of tissue macrophages and monocyte populations 57 . Perivascular macrophages (PVMs) are brain macrophages that originate from hematopoietic precursors cells, express the mannose receptor (CD206 + ) and reside in the perivascular space of penetrating vessels 58 , 59 . Activation of PVMs subsequent to BBB leakage has been shown to induce the production of ROS 41 , 60 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological depletion of microglia and perivascular macrophages prevents vascular Cognitive Impairment in Ang II-induced Hypertension

Kerkhofs¹,

Hagen²,

Milanova³

et al. 2020

Theranostics

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Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1 gfp/wt x Thy1 yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages. Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia /PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

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Vessel-Associated Immune Cells in Cerebrovascular Diseases: From Perivascular Macrophages to Vessel-Associated Microglia

Cited by 68 publications

References 65 publications

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Shedding Light on the Dark Side of the Microglia

Pharmacological depletion of microglia and perivascular macrophages prevents vascular Cognitive Impairment in Ang II-induced Hypertension

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