Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response

Bachiller, Sara; Jiménez-Ferrer, Itzia; Paulus, Agnes; Yang, Yiyi; Swanberg, Maria; Deierborg, Tomas; Boza-Serrano, Antonio

doi:10.3389/fncel.2018.00488

Cited by 572 publications

(425 citation statements)

References 220 publications

(266 reference statements)

Supporting

Mentioning

413

Contrasting

Unclassified

Order By: Relevance

“…In fact, the microglia exhibited increased metabolic upregulation from multiple energy sources. RNA sequencing of microglia in neurodegenerative disease has shown that microglial exhibit more nuanced states than these simple M1 and M2 polar opposites (14,85,(91)(92)(93). There is also evidence to suggest that dysregulation of metabolism and accumulation of mt-DNA mutations within microglia may itself be a trigger for microglial activation in neurodegenerative disease (94).…”

Section: Discussionmentioning

confidence: 99%

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

Tribble

Harder

Williams

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia early following ocular hypertensive insults is unknown. Methods:To elucidate the molecular identity of microglia during early glaucoma pathogenesis, we performed RNA-sequencing of microglia mRNA from the optic nerve head of a genetic mouse model of glaucoma (DBA/2J) at a time point following ocular hypertensive insults, but preceding detectable neurodegeneration (with microglia identified as being CD45 lo /CD11b + /CD11c -). Transcriptomic profiles were compared to other published optic nerve head datasets to assess the contribution of microglia to the signatures discovered in these published data. Furthermore, RNAsequencing was performed on optic nerve head microglia from mice treated with radiation therapy, a potent therapy preventing neuroinflammatory insults.Results: Transcriptomic profiling of optic nerve head microglia mRNA identifies early metabolic priming with marked changes to mitochondria-derived RNA expression, and changes to phagocytosis, inflammatory, and sensome pathways. Comparative analysis of these data with data from previously published whole optic nerve head tissue or monocyte-only samples from DBA/2J mice demonstrate that many of the neuroinflammatory signatures in these data sets arise from infiltrating monocytes and not reactive microglia. Finally, radiation therapy of DBA/2J mice potently abolishes these microglia metabolic transcriptomic changes at the same time points. Conclusions:Microglia become metabolically primed early in glaucoma pathogenesis with suppression of homeostatic regulation including phagocytosis, inflammatory, and sensome pathways. These changes are largely prevented by radiation therapy. Neuroinflammatory signatures in DBA/2J glaucoma likely arise from infiltrating monocytes and not from activated or proliferative microglia at this early time point. In addition, our data provide a unique resource for the community to help drive further hypothesis generation and testing. (Figure 3D-F) showed that radiation treatment affects phagocytosis, metabolism, mitochondria, and inflammation related genes, all pathways altered in microglia (see above). There were 579 genes altered by radiation that overlapped with changes in glaucoma (D2 vs. D2-Gpnmb + comparison). For 578 of these genes, radiation treatment corrected the disease-related change (Figure 3G). Dcbld2 was the single gene DE downregulated in both datasets. Dcbld2 encodes the endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) which is upregulated in endothelial cells following vascular injury (53). Its deletion or downregulation impairs retinal angiogenesis (54) and ...

show abstract

Section: Discussionmentioning

confidence: 99%

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

Tribble

Harder

Williams

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…However, microglia can mediate beneficial and detrimental neuroinflammatory mechanisms during disease. Indeed, because microglia are transcriptionally diverse and highly responsive to their environment (Dubbelaar et al, 2018), they contextually respond to acute and chronic tissues disease states determined by both the primary disease mechanism and disease duration (Bachiller et al, 2018; Tay et al, 2017). In general, detrimental consequences of microglial responses in AD are mediated by pro-inflammatory mechanisms, which include release of neurotoxic molecules (ROS, NO), production of cytokines (IL1β, TNFα, IL6), phagocytosis of live neurons or of healthy synapses and dendrites, impaired phagocytic clearance of debris and pathological protein aggregates.…”

Section: Introductionmentioning

confidence: 99%

Microglial ERK signaling is a critical regulator of pro-inflammatory immune responses in Alzheimer’s disease

Ramesha

et al. 2019

Preprint

View full text Add to dashboard Cite

BackgroundThe mitogen-activated protein kinase (MAPK) pathway is a central regulator of gene expression, pro-survival signaling, and inflammation. However, the importance of MAPK pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's Disease (AD) remains unclear. Here we examined the role of MAPK signaling in microglia using pre-clinical in-vitro and in-vivo models of AD pathology integrated with quantitative proteomics studies of postmortem human brains. MethodsWe performed multiplexed immunoassay analyses of MAPK phosphoproteins, particularly ERK1/2, in acutely-isolated microglia and brain tissue from wild-type and 5xFAD mice.Neuropathological studies of mouse and human brain tissues were performed to quantify total and phosphorylated ERK protein in AD. The importance of ERK signaling in unstimulated and interferon γ (IFNγ)-stimulated primary microglia cultures was investigated using NanoString transcriptomic profiling, coupled with functional assays of amyloid β (Αβ) and neuronal phagocytosis. Receptor tyrosine kinases (RTKs) likely responsible for ERK signaling in homeostatic microglia and disease-associated-microglia (DAM) states and ERK-regulated human AD risk genes were identified using gene expression data. Total and phosphorylated MAPKs in human post-mortem brain tissues were measured in quantitative proteomic datasets. ResultsPhosphorylated ERK was the most strongly up-regulated signaling protein within the MAPK pathway in microglia acutely isolated from 5xFAD brains. Neuroinflammatory transcriptomic and phagocytic profiling of mouse microglia confirmed that ERK is a critical regulator of IFNγmediated pro-inflammatory activation of microglia, although it was also important for constitutive microglial functions. Phospho-ERK was an upstream regulator of disease-associated microglia (DAM) gene expression (Trem2, Tyrobp), as well as of several human AD risk genes (Bin1, Cd33, Trem2, Cnn2). Among RTKs that signal via ERK, CSF1R and MERTK were primarily expressed by homeostatic microglia while AXL and FLT1 were likely regulators of ERK signaling in DAM. Within DAM, FLT4 and IGF1R were specifically expressed by proand anti-inflammatory DAM sub-profiles respectively. In quantitative proteomic analyses of post-mortem human brain from non-disease, asymptomatic and cognitively-impaired AD cases, 3 ERK1 and ERK2 were the only MAPK pathway signaling proteins with increased protein expression and positive associations with neuropathological grade. Moreover, in a phosphoproteomic study of post-mortem human brains from controls, asymptomatic and symptomatic AD cases, we found evidence for a progressive increased flux through the ERK signaling pathway. ConclusionsOur integrated analyses using pre-clinical models and human proteomic data strongly suggest that ERK phosphorylation in microglia is a critical regulator of pro-inflammatory immune response in AD pathogenesis and that modulation of ERK via upstream RTKs may reveal novel avenues for immunomodulation. 5 are typically receptors for gro...

show abstract

“…The deposition of α -syn causes AST to produce pro-inflammatory cytokines and activate MG, suggesting a plausible role of AST in the initiation of PD 23, 24 . Given that AST and MG are two primary cell types that closely involved in neuroinflammation 43 , we next focused on AST and MG to explore the neuroinflammatory reactions at early stage of PD. Transcriptomic changes of MB_MG under pathological state were not compelling, with only 87 down-regulated genes and none up-regulated genes (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

Zhong

Tang

Zhu

et al. 2020

Preprint

View full text Add to dashboard Cite

Parkinson's disease (PD) is a neurodegenerative disease leading to the impairment 24 of execution of movement. PD pathogenesis has been largely investigated, but either restricted 25 in bulk level or at certain cell types, which failed to capture cellular heterogeneity and intrinsic 26 interplays among distinct cell types. To overcome this, we applied single-nucleus RNA-seq 27 and single cell ATAC-seq on cerebellum, midbrain and striatum of PD mouse and matched 28 control. With 74,493 cells in total, we comprehensively depicted the dysfunctions under PD 29 pathology covering proteostasis, neuroinflammation, calcium homeostasis and extracellular 30 neurotransmitter homeostasis. Besides, by multi-omics approach, we identified putative 31 biomarkers for early stage of PD, based on the relationships between transcriptomic and 32 epigenetic profiles. We located certain cell types that primarily contribute to PD early 33 pathology, narrowing the gap between genotypes and phenotypes. Taken together, our study 34 provides a valuable resource to dissect the molecular mechanism of PD pathogenesis at single 35 cell level, which could facilitate the development of novel methods regarding diagnosis, 36 monitoring and practical therapies against PD at early stage. 37 38 39 Plenty of studies have made great progress in disentangling the link between -syn 52 oligomerization and neuron death, revealing pathways including proteostasis, mitochondrial 53 dysfunction, neuroinflammation and so on 4 . Nevertheless, the majority of previously studies 54 were conducted at tissue level. Wassouf's team performed RNA-seq on 6-month-old mice 55 overexpressing SNCA ( -syn encoding gene) and found that striatal gene expression profiles 56 3 were greatly disrupted, whose functions were primarily related to neuroinflammation and 57 synaptic plasticity 5 . Richard et. al. combined bulk and single-cell RNA-seq for iPSC-derived 58 dopamine neurons with a GBA mutation and identified HDAC4 as a potential therapeutic PD 59 target 6 . Given the fact that intricate interplay across and within cell types jointly contributes to 60 PD pathogenesis 7 , it is essential to interrogate cell-resolution information in order to unveil the 61 possible PD-related and PD-causing molecular circuits. Single cell sequencing technologies 62 have facilitated the researches in various fields, providing us an opportunity to capture subtler 63 changes that may be masked by bulk sequencing. 64 65Of note, due to synaptic plasticity, 80% of dopaminergic neurons in SN have been lost before 66 any diagnosable symptoms of PD occur 8 . Hence, this raises the necessity to dissect cellular 67 changes in the early stage of PD and identify corresponding markers, ultimately allowing the 68 development of novel early interventions. Nigrostriatal dopamine pathway malfunction 69 attributes largely to PD pathologies 9 . Besides, cerebellum is the pivot of motor coordination 70 but has been often overlooked in Parkinsonism. Therefore, with the aim to explore the 71 deregulation in early sta...

show abstract

Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response

Cited by 572 publications

References 220 publications

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

Microglial ERK signaling is a critical regulator of pro-inflammatory immune responses in Alzheimer’s disease

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

Contact Info

Product

Resources

About