Association Between Toll‐Like Receptor 4 (<i>TLR4</i>) and Triggering Receptor Expressed on Myeloid Cells 2 (<i>TREM2</i>) Genetic Variants and Clinical Progression of Huntington's Disease

Vuono, Romina; Kouli, Antonina; Legault, Emilie M.; Chagnon, Lauriane; Allinson, Kieren; Spada, Alberto; Biunno, Ida; Barker, Roger A.; Drouin‐Ouellet, Janelle

doi:10.1002/mds.27911

Cited by 14 publications

(13 citation statements)

References 57 publications

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“…Notably, in these same brain regions in PD, we also observed increased expression of IL-1β, a downstream product of the inflammasome pathway which is triggered by TLR4 activation. Interestingly, TLR2 and TLR4 have also been implicated in other proteinopathies, including Alzheimer's [69] and Huntington's disease [73] raising the possibility of a common pathogenic mechanism across several neurodegenerative diseases. The concomitant increase in the gene expression of TLR4 and IL-1β in the substantia nigra and the frontal cortex suggests an involvement of the NODlike receptor protein 3 (NLRP3) inflammasome in these regions, with TLR4 activation resulting in increased expression of pro-IL-1β as well as NLRP3 activation; in turn, NLRP3 inflammasome activation could be responsible for the cleavage of pro-IL1β to the mature protein.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Kouli

Camacho

Allinson

et al. 2020

acta neuropathol commun

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112

107

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Parkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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Section: Discussionmentioning

confidence: 99%

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Kouli

Camacho

Allinson

et al. 2020

acta neuropathol commun

Self Cite

112

107

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“…Another report of Alzheimer's disease is that the significantly decreased plaque load observed in APP transgenic and APOE or TREM2 knockout mice (Krasemann et al, 2017). At the same time, TREM2 is a potential genetic modifier of Huntington's disease (HD), and its expression is related to the TLR4 receptor (Vuono et al, 2020). In vascular dementia (VD), TREM2 regulates the microglial activation phenotype to improve disease progression (Wang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Huang

Yan

et al. 2021

Front. Neurosci.

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Parkinson’s disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

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“…In contrast to what has been reported for Trem1, activation of Trem2 results in a diminished endogenous inflammatory response 54 . In studies carried out in monocytes and microglial cells, Trem2 was found to interact with bacterial cell surface carbohydrates 55,56 and to down‐modulate TLR‐mediated cellular activation 29–31 . While both Trem1 and TremL2 have been detected on neutrophils, 57 no previous reports document the expression and/or function of Trem or Trem‐like proteins in human or mouse eosinophils.…”

Section: Resultsmentioning

confidence: 89%

“…Trem2 has been characterized primarily on monocytes, dendritic cells, and microglia. Trem2 promotes cell proliferation and differentiation 26–28 and limits inflammation via modulation of TLR responses 29–31 …”

Section: Introductionmentioning

confidence: 99%

Differential expression of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) in tissue eosinophils

Sek

Percopo

Boddapati

et al. 2021

Journal of Leukocyte Biology

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No longer regarded simply as end‐stage cytotoxic effectors, eosinophils are now recognized as complex cells with unique phenotypes that develop in response stimuli in the local microenvironment. In our previous study, we documented eosinophil infiltration in damaged muscle characteristic of dystrophin‐deficient (mdx) mice that model Duchenne muscular dystrophy. Specifically, we found that eosinophils did not promote the generation of muscle lesions, as these persisted in eosinophil‐deficient mdx.PHIL mice. To obtain additional insight into these findings, we performed RNA sequencing of eosinophils isolated from muscle tissue of mdx, IL5tg, and mdx.IL5tg mice. We observed profound up‐regulation of classical effector proteins (major basic protein‐1, eosinophil peroxidase, and eosinophil‐associated ribonucleases) in eosinophils isolated from lesion‐free muscle from IL5tg mice. By contrast, we observed significant up‐regulation of tissue remodeling genes, including proteases, extracellular matrix components, collagen, and skeletal muscle precursors, as well as the immunomodulatory receptor, Trem2, in eosinophils isolated from skeletal muscle tissue from the dystrophin‐deficient mdx mice. Although the anti‐inflammatory properties of Trem2 have been described in the monocyte/macrophage lineage, no previous studies have documented its expression in eosinophils. We found that Trem2 was critical for full growth and differentiation of bone marrow‐derived eosinophil cultures and full expression of TLR4. Immunoreactive Trem2 was also detected on human peripheral blood eosinophils at levels that correlated with donor body mass index and total leukocyte count. Taken together, our findings provide important insight into the immunomodulatory and remodeling capacity of mouse eosinophils and the flexibility of their gene expression profiles in vivo.

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Association Between Toll‐Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease

Cited by 14 publications

References 57 publications

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Differential expression of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) in tissue eosinophils

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