<i>Trem2</i>promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Liu, Wenfei; Taso, Orjona; Wang, Rui; Garcia-Reitboeck, Pablo; Andrews, William D.; Piers, Thomas M.; Pocock, Jennifer M.; Cummings, Damian M.; Hardy, John; Edwards, Frances A.; Salih, Dervis A.

doi:10.1101/449884

Cited by 3 publications

(2 citation statements)

References 128 publications

(118 reference statements)

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“…Knocking out Trem2 in 5xFAD mice causes dampening of both pro- and anti-inflammatory networks [120]. Liu et al described an anti-inflammatory Trem2 network encompassing known AD risk genes such as SPI1 , MS4A6A , and CD33 , which responds to amyloid build-up [134]. Therefore, it has also been suggested that the activation of this anti-inflammatory gene network can occur in response to amyloid build-up as a protective mechanism.…”

Section: Advancements In Transcriptomics and Gene Network Analysismentioning

confidence: 99%

Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Chew

Petretto

2019

Genes

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Microglia, the main immune cells of the central nervous system, are increasingly implicated in Alzheimer’s disease (AD). Manifold transcriptomic studies in the brain have not only highlighted microglia’s role in AD pathogenesis, but also mapped crucial pathological processes and identified new therapeutic targets. An important component of many of these transcriptomic studies is the investigation of gene expression networks in AD brain, which has provided important new insights into how coordinated gene regulatory programs in microglia (and other cell types) underlie AD pathogenesis. Given the rapid technological advancements in transcriptional profiling, spanning from microarrays to single-cell RNA sequencing (scRNA-seq), tools used for mapping gene expression networks have evolved to keep pace with the unique features of each transcriptomic platform. In this article, we review the trajectory of transcriptomic network analyses in AD from brain to microglia, highlighting the corresponding methodological developments. Lastly, we discuss examples of how transcriptional network analysis provides new insights into AD mechanisms and pathogenesis.

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Section: Advancements In Transcriptomics and Gene Network Analysismentioning

confidence: 99%

Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Chew

Petretto

2019

Genes

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“…Trem2 is a membrane-traversing protein from the immunoglobulin superfamily, expressed on macrophages, dendritic cells, and other cell types derived from the myeloid lineage (Liu et al, 2020). In CNS, Trem2 is predominantly expressed on microglia, which mediates phagocytosis and cell activation upon lipid binding (Wang, Mustafa, et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

Pang,

Chu,

Zhou

et al. 2023

Journal of Neurochemistry

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Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic‐lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic‐lysosomal pathway, leading to microglial polarization towards anti‐inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic‐lysosomal activation in hypoperfusion‐induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.image

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Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer’s disease-like pathology?

et al. 2020

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Adipose tissue is an active metabolic organ that contributes to processes such as energy storage and utilization and to the production of a number of metabolic agents, such as adipokines, which play a role in inflammation. In this review, we try to elucidate the connections between peripheral inflammation at obesity and Type 2 diabetes and the central inflammatory process. Multiple lines of evidence highlight the importance of peripheral inflammation and its link to neuroinflammation, which can lead to neurodegenerative diseases such as dementia, Alzheimer’s disease (AD) and Parkinson’s disease. In addition to the accumulation of misfolded amyloid beta (Aβ) peptide and the formation of the neurofibrillary tangles of hyperphosphorylated tau protein in the brain, activated microglia and reactive astrocytes are the main indicators of AD progression. They were found close to Aβ plaques in the brains of both AD patients and rodent models of Alzheimer’s disease-like pathology. Cytokines are key players in pro- and anti-inflammatory processes and are also produced by microglia and astrocytes. The interplay of seemingly unrelated pathways between the periphery and the brain could, in fact, have a common denominator, with inflammation in general being a key factor affecting neuronal processes in the brain. An increased amount of white adipose tissue throughout the body seems to be an important player in pro-inflammatory processes. Nevertheless, other important factors should be studied to elucidate the pathological processes of and the relationship among obesity, Type 2 diabetes and neurodegenerative diseases.

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Trem2promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Cited by 3 publications

References 128 publications

Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion

Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer’s disease-like pathology?

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