Suppressor of Cytokine Signaling 3: Emerging Role Linking Central Insulin Resistance and Alzheimer’s Disease

Cao, Lan; Wang, Zigao; Wan, Wenbin

doi:10.3389/fnins.2018.00417

Cited by 31 publications

(27 citation statements)

References 89 publications

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“…A previous study demonstrated the role of GBP protein in the formation of inflammasome complex as well as its anti-inflammatory and autoimmunity-controlling effect [ 39 ], yet the specific function of the GBP protein family remains to be discovered. SOCS3, promoted by IFN-γ downstream genes STAT1 or STAT3 [ 40 , 41 ], is known as a negative regulator of cytokine signaling and participant in control of CNS immunity [ 42 , 43 ]. CCL2 is the key chemokine that recruits myeloid-derived cells to the tumor microenvironment in glioma [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy

Qian

Wang

et al. 2018

J Neuroinflammation

206

161

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BackgroundPD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies.MethodsThe distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival.ResultsThe distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-γ level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-γ induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-γ-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-γ level. By combining the relative expression of the listed IFN-γ-induced genes, IFN-γ score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies.ConclusionOur study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-γ is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-γ score aggregated from the expressions of the listed IFN-γ-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1330-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy

Qian

Wang

et al. 2018

J Neuroinflammation

206

161

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“…Therefore, the role of SATA3 in stroke is still controversial. In addition, suppressor of cytokine signaling 3 (SOCS3) has been identified to have an emerging role linking central insulin resistance and Alzheimer's disease, but the relationship between SOCS3 and stroke has not been studied sufficiency [31].…”

Section: Discussionmentioning

confidence: 99%

Identification of novel biomarkers in ischemic stroke: a genome-wide integrated analysis

et al. 2020

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Background: Ischemic Stroke (IS) is the most common neurological emergency disease and has become the second most frequent cause of death after coronary artery disease in 2015. Owing to its high fatality rate and narrow therapeutic time window, early identification and prevention of potential stroke is becoming increasingly important. Methods: We used meta-analysis and bioinformatics mining to explore disease-related pathways and regulatory networks after combining messengerRNA (mRNA) and miRNA expression analyses. The purpose of our study was to screen for candidate target genes and microRNA(miRNA) for early diagnosis of potential stroke. Results: Five datasets were collected from the Gene Expression Omnibus (GEO) database by systematical retrieval, which contained three mRNA datasets (102 peripheral blood samples in total) and two miRNA dataset (59 peripheral blood samples). Approximately 221 different expression(DE) mRNAs (155 upregulated and 66 downregulated mRNAs) and 185 DE miRNAs were obtained using the metaDE package and GEO2R tools. Further functional enrichments of DE-mRNA, DE-miRNA and protein-protein interaction (PPI) were performed and visualized using Cytoscape. Conclusion: Our study identified six core mRNAs and two regulated miRNAs in the pathogenesis of stroke, and we elaborated the intrinsic role of systemic lupus erythematosus (SLE) and atypical infections in stroke, which may aid in the development of precision medicine for treating ischemic stroke. However, the role of these novel biomarkers and the underlying molecular mechanisms in IS require further fundamental experiments and further clinical evidence.

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“…Thus, SOCS3 was a good candidate to negatively regulate insulin signaling at early time-points, prior to the delayed (7 days) insulin resistance that we found. Furthermore, SOCS3 expression has been found to be upregulated in the CNS of AD patients 35 .…”

Section: Discussionmentioning

confidence: 99%

Chronic synaptic insulin resistance after traumatic brain injury abolishes insulin protection from amyloid beta and tau oligomer-induced synaptic dysfunction

Franklin

Krishnan

Taglialatela

2019

Sci Rep

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Traumatic brain injury (TBI) is a risk factor for Alzheimer’s disease (AD), although the mechanisms contributing to this increased risk are unknown. Insulin resistance is an additional risk factor for AD whereby decreased insulin signaling increases synaptic sensitivity to amyloid beta (Aβ) and tau. Considering this, we used rats that underwent a lateral fluid percussion injury at acute and chronic time-points to investigate whether decreased insulin responsiveness in TBI animals is playing a role in synaptic vulnerability to AD pathology. We detected acute and chronic decreases in insulin responsiveness in isolated hippocampal synaptosomes after TBI. In addition to assessing both Aβ and tau binding on synaptosomes, we performed electrophysiology to assess the dysfunctional impact of Aβ and tau oligomers as well as the protective effect of insulin. While we saw no difference in binding or degree of LTP inhibition by either Aβ or tau oligomers between sham and TBI animals, we found that insulin treatment was able to block oligomer-induced LTP inhibition in sham but not in TBI animals. Since insulin treatment has been discussed as a therapy for AD, this gives valuable insight into therapeutic implications of treating AD patients based on one’s history of associated risk factors.

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Suppressor of Cytokine Signaling 3: Emerging Role Linking Central Insulin Resistance and Alzheimer’s Disease

Cited by 31 publications

References 89 publications

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy

Identification of novel biomarkers in ischemic stroke: a genome-wide integrated analysis

Chronic synaptic insulin resistance after traumatic brain injury abolishes insulin protection from amyloid beta and tau oligomer-induced synaptic dysfunction

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