International Journal of Molecular Sciences

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Open AccessEditorial

Special Issue “Microglia Heterogeneity and Its Relevance for Translational Research”

by Alessandro Michelucci, Veronique E. Miron and Josef Priller

Int. J. Mol. Sci. 2021, 22(22), 12350; https://doi.org/10.3390/ijms222212350 - 16 Nov 2021

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Abstract

Microglia are necessary for the development and function of the central nervous system (CNS) [...] Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

Research

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21 pages, 3819 KiB

Open AccessArticle

Immunohistochemical Study of ASC Expression and Distribution in the Hippocampus of an Aged Murine Model of Alzheimer’s Disease

by Diana Reimers, Manuela Vallejo-Muñoz, María José Casarejos, Adriano Jimenez-Escrig, Rafael Gonzalo-Gobernado and Eulalia Bazan

Int. J. Mol. Sci. 2021, 22(16), 8697; https://doi.org/10.3390/ijms22168697 - 13 Aug 2021

Cited by 9 | Viewed by 3216

Abstract

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) [...] Read more.

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) and leads to the generation of potent pro-inflammatory cytokines. The protein “apoptosis-associated speck-like protein containing a caspase recruitment domain” (ASC) modulates IF activation but has also other functions which are crucial in AD. We intended to characterize immunohistochemically ASC and pattern recognition receptors (PRR) of IF in the hippocampus (HP) of the transgenic mouse model Tg2576 (APP), in which amyloid-beta (Aβ) pathology is directly dependent on age. We show in old-aged APP a significant amount of ASC in microglia and astrocytes associated withAβ plaques, in the absence of PRR described by others in glial cells. In addition, APP developed foci with clusters of extracellular ASC granules not spatiallyrelated to Aβ plaques, which density correlated with the advanced age of mice and AD development. Clusters were associated withspecific astrocytes characterized by their enlarged ring-shaped process terminals, ASC content, and frequent perivascular location. Their possible implication in ASC clearance and propagation of inflammation is discussed. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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21 pages, 4818 KiB

Open AccessArticle

Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

by Maddalena Grieco, Maria Giovanna De Caris, Elisa Maggi, Federica Armeli, Roberto Coccurello, Tiziana Bisogno, Maria D’Erme, Mauro Maccarrone, Patrizia Mancini and Rita Businaro

Int. J. Mol. Sci. 2021, 22(14), 7711; https://doi.org/10.3390/ijms22147711 - 19 Jul 2021

Cited by 30 | Viewed by 4539

Abstract

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model [...] Read more.

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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21 pages, 4452 KiB

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Microglial Heterogeneity and Its Potential Role in Driving Phenotypic Diversity of Alzheimer’s Disease

by Stefano Sorrentino, Roberto Ascari, Emanuela Maderna, Marcella Catania, Bernardino Ghetti, Fabrizio Tagliavini, Giorgio Giaccone and Giuseppe Di Fede

Int. J. Mol. Sci. 2021, 22(5), 2780; https://doi.org/10.3390/ijms22052780 - 9 Mar 2021

Cited by 13 | Viewed by 4343

Abstract

Alzheimer’s disease (AD) is increasingly recognized as a highly heterogeneous disorder occurring under distinct clinical and neuropathological phenotypes. Despite the molecular determinants of such variability not being well defined yet, microglial cells may play a key role in this process by releasing distinct [...] Read more.

Alzheimer’s disease (AD) is increasingly recognized as a highly heterogeneous disorder occurring under distinct clinical and neuropathological phenotypes. Despite the molecular determinants of such variability not being well defined yet, microglial cells may play a key role in this process by releasing distinct pro- and/or anti-inflammatory cytokines, potentially affecting the expression of the disease. We carried out a neuropathological and biochemical analysis on a series of AD brain samples, gathering evidence about the heterogeneous involvement of microglia in AD. The neuropathological studies showed differences concerning morphology, density and distribution of microglial cells among AD brains. Biochemical investigations showed increased brain levels of IL-4, IL-6, IL-13, CCL17, MMP-7 and CXCL13 in AD in comparison with control subjects. The molecular profiling achieved by measuring the brain levels of 25 inflammatory factors known to be involved in neuroinflammation allowed a stratification of the AD patients in three distinct “neuroinflammatory clusters”. These findings strengthen the relevance of neuroinflammation in AD pathogenesis suggesting, in particular, that the differential involvement of neuroinflammatory molecules released by microglial cells during the development of the disease may contribute to modulate the characteristics and the severity of the neuropathological changes, driving—at least in part—the AD phenotypic diversity. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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16 pages, 3395 KiB

Open AccessArticle

Underestimated Peripheral Effects Following Pharmacological and Conditional Genetic Microglial Depletion

by Jinming Han, Yueshan Fan, Kai Zhou, Keying Zhu, Klas Blomgren, Harald Lund, Xing-Mei Zhang and Robert A. Harris

Int. J. Mol. Sci. 2020, 21(22), 8603; https://doi.org/10.3390/ijms21228603 - 15 Nov 2020

Cited by 28 | Viewed by 4927

Abstract

Microglia, predominant parenchymal resident macrophages in the central nervous system (CNS), are crucial players in neurodevelopment and CNS homeostasis. In disease conditions, pro-inflammatory microglia predominate over their regulatory counterparts, and are thus a potential immunotherapeutic target. It has been well documented that microglia [...] Read more.

Microglia, predominant parenchymal resident macrophages in the central nervous system (CNS), are crucial players in neurodevelopment and CNS homeostasis. In disease conditions, pro-inflammatory microglia predominate over their regulatory counterparts, and are thus a potential immunotherapeutic target. It has been well documented that microglia can be effectively depleted using both conditional genetic Cx3cr1^Cre-diphtheria toxin receptor (DTR)/diphtheria toxin subunit A (DTA) animal models and pharmacological colony-stimulating factor 1 receptor (CSF1R) inhibitors. Recent advances using these approaches have expanded our knowledge of the multitude of tasks conducted by microglia in both homeostasis and diseases. Importantly, experimental microglial depletion has been proven to exert neuroprotective effects in an increasing number of disease models, mostly explained by reduced neuroinflammation. However, the comprehensive effects of additional targets such as circulating monocytes and peripheral tissue macrophages during microglial depletion periods have not been investigated widely, and for those studies addressing the issue the conclusions are mixed. In this study, we demonstrate that experimental microglial depletion using both Cx3cr1^CreER/+Rosa26^DTA/+ mice and different doses of CSF1R inhibitor PLX3397 exert crucial influences on circulating monocytes and peripheral tissue macrophages. Our results suggest that effects on peripheral immunity should be considered both in interpretation of microglial depletion studies, and especially in the potential translation of microglial depletion and replacement therapies. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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Review

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18 pages, 1976 KiB

Open AccessReview

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

by Teodora Larisa Timis, Ioan Alexandru Florian, Sergiu Susman and Ioan Stefan Florian

Int. J. Mol. Sci. 2021, 22(11), 6141; https://doi.org/10.3390/ijms22116141 - 7 Jun 2021

Cited by 11 | Viewed by 4761

Abstract

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their [...] Read more.

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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23 pages, 1675 KiB

Open AccessReview

The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease

by Katja Badanjak, Sonja Fixemer, Semra Smajić, Alexander Skupin and Anne Grünewald

Int. J. Mol. Sci. 2021, 22(9), 4676; https://doi.org/10.3390/ijms22094676 - 28 Apr 2021

Cited by 182 | Viewed by 14010

Abstract

With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that [...] Read more.

With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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24 pages, 969 KiB

Open AccessReview

Microglia Diversity in Healthy and Diseased Brain: Insights from Single-Cell Omics

by Natalia Ochocka and Bozena Kaminska

Int. J. Mol. Sci. 2021, 22(6), 3027; https://doi.org/10.3390/ijms22063027 - 16 Mar 2021

Cited by 52 | Viewed by 10020

Abstract

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to [...] Read more.

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to the ability of microglia to adapt a context-specific phenotype. Numerous gene expression profiling studies of immunosorted CNS immune cells did not permit a clear dissection of their phenotypes, particularly in diseases when peripheral cells of the immune system come to play. Only recent advances in single-cell technologies allowed studying microglia at high resolution and revealed a spectrum of discrete states both under homeostatic and pathological conditions. Single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (Cytometry by Time-Of-Flight, CyTOF) enabled determining entire transcriptomes or the simultaneous quantification of >30 cellular parameters of thousands of individual cells. Single-cell omics studies demonstrated the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies: neurodegenerative disorders, stroke, depression, and brain tumors. We summarize the findings from those studies and the current state of knowledge of functional diversity of microglia under physiological and pathological conditions. A precise definition of microglia functions and phenotypes may be essential to design future immune-modulating therapies. Full article

(This article belongs to the Special Issue Microglia Heterogeneity and Its Relevance for Translational Research)

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