RNA binding protein RPS3 mediates microglial polarization by activating NLRP3 inflammasome via SIRT1 in ischemic stroke

Zhou, Dimi; Chen, Lin; Wang, Yuzheng; Gan, Lu; Yuan, Ming; Zhang, Lei; Chen, Fenfang

doi:10.1016/j.jstrokecerebrovasdis.2023.107132

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…6 D, Additional file 9 : Table S9). Notably, signature genes of FDAMic, including those implicated in microglial cell proliferation (i.e., CD74 [ 99 ], CSF1R [ 46 ] and RPS3 [ 109 ]), LOAD pathogenesis (i.e., TYROBP [ 63 ] and SPI1 [ 110 ]) and immune checkpoint signaling (i.e., VSIG4 [ 111 ]), were the most upregulated in the APOE34/44 group, specifically among females (Fig. 6 E).…”

Section: Resultsmentioning

confidence: 99%

Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease

Wu,

Bi,

Chow

2024

J Neuroinflammation

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Background Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined. Methods In-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted. Results The relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-β binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia. Conclusion This study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development.

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Section: Resultsmentioning

confidence: 99%

Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease

Wu,

Bi,

Chow

2024

J Neuroinflammation

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“…Specifically, The NLRP3 inflammasome is among the most prominent inflammasomes, with high expression levels in the brain, as it plays a crucial role in detecting cell damage and initiating an inflammatory cascade. Several studies have indicated that the NLRP3 inflammasome plays an essential part in the occurrence and development of cerebral I/R injury ( Heinisch et al, 2022 ; Kerr et al, 2022 ), and the activation of Sirt1 can exert the neuroprotection via inhibition of this pathway ( Zhou et al, 2023 ).…”

Section: Potential Mechanisms Of Sirt1 For Ischemic Strokementioning

confidence: 99%

New insights into Sirt1: potential therapeutic targets for the treatment of cerebral ischemic stroke

Tang

Wen

Qin

et al. 2023

Front. Cell. Neurosci.

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Ischemic stroke is one of the main causes of mortality and disability worldwide. However, the majority of patients are currently unable to benefit from intravenous thrombolysis or intravascular mechanical thrombectomy due to the limited treatment windows and serious complications. Silent mating type information regulation 2 homolog 1 (Sirt1), a nicotine adenine dinucleotide-dependent enzyme, has emerged as a potential therapeutic target for ischemic stroke due to its ability to maintain brain homeostasis and possess neuroprotective properties in a variety of pathological conditions for the central nervous system. Animal and clinical studies have shown that activation of Sirt1 can lessen neurological deficits and reduce the infarcted volume, offering promise for the treatment of ischemic stroke. In this review, we summarized the direct evidence and related mechanisms of Sirt1 providing neuroprotection against cerebral ischemic stroke. Firstly, we introduced the protein structure, catalytic mechanism and specific location of Sirt1 in the central nervous system. Secondly, we list the activators and inhibitors of Sirt1, which are primarily divided into three categories: natural, synthetic and physiological. Finally, we reviewed the neuroprotective effects of Sirt1 in ischemic stroke and discussed the specific mechanisms, including reducing neurological deficits by inhibiting various programmed cell death such as pyroptosis, necroptosis, ferroptosis, and cuproptosis in the acute phase, as well as enhancing neurological repair by promoting angiogenesis and neurogenesis in the later stage. Our review aims to contribute to a deeper understanding of the critical role of Sirt1 in cerebral ischemic stroke and to offer novel therapeutic strategies for this condition.

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Transcutaneous electrical acupoint stimulation attenuated neuroinflammation and oxidative stress by activating SIRT1-induced signaling pathway in MCAO/R rat models

Tan,

Dong,

et al. 2024

Experimental Neurology

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RNA binding protein RPS3 mediates microglial polarization by activating NLRP3 inflammasome via SIRT1 in ischemic stroke

Cited by 6 publications

References 34 publications

Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease

Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease

New insights into Sirt1: potential therapeutic targets for the treatment of cerebral ischemic stroke

Transcutaneous electrical acupoint stimulation attenuated neuroinflammation and oxidative stress by activating SIRT1-induced signaling pathway in MCAO/R rat models

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