Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

Ahmadabad, Rezan Ashayeri; Mirzaasgari, Zahra; Gorji, Ali; Ghadiri, Maryam Khaleghi

doi:10.3390/ijms22116153

Cited by 26 publications

(16 citation statements)

References 243 publications

(296 reference statements)

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“…Among the receptors involved in microglial M1 polarization are TLR4 receptors [ 266 ]. In preclinical studies, the inhibition of TLR4 resulted in reduced infarct size and improved recovery in diabetic rats [ 267 ] A phase 1b/2a trial (NCT 04734548) is currently recruiting 151 patients eligible for endovascular treatment to evaluate the safety of inhibiting TLR4 receptors with ApTOLL [ 268 ].…”

Section: Therapeutic Approaches Focusing On Modulation Of Neuroinflammationmentioning

confidence: 99%

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

Jurcău

Simion

2021

IJMS

157

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Its increasing incidence has led stroke to be the second leading cause of death worldwide. Despite significant advances in recanalization strategies, patients are still at risk for ischemia/reperfusion injuries in this pathophysiology, in which neuroinflammation is significantly involved. Research has shown that in the acute phase, neuroinflammatory cascades lead to apoptosis, disruption of the blood–brain barrier, cerebral edema, and hemorrhagic transformation, while in later stages, these pathways support tissue repair and functional recovery. The present review discusses the various cell types and the mechanisms through which neuroinflammation contributes to parenchymal injury and tissue repair, as well as therapeutic attempts made in vitro, in animal experiments, and in clinical trials which target neuroinflammation, highlighting future therapeutic perspectives.

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Section: Therapeutic Approaches Focusing On Modulation Of Neuroinflammationmentioning

confidence: 99%

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

Jurcău

Simion

2021

IJMS

157

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“…After ischemic stroke, IL-17 was activated in the damaged brain areas and broke the blood brain barrier via producing massive reactive oxygen species, thereby contributing to neurodegeneration [ 54 ]. NOD-like and Toll-like receptors were reported to stimulate inflammatory responses in IS; some pharmacological agents targeting these receptors have been investigated specifically [ 55 , 56 ]; however, few of these agents translate into clinical practices despite some inspiring discoveries.…”

Section: Discussionmentioning

confidence: 99%

Investigating the AC079305/DUSP1 Axis as Oxidative Stress-Related Signatures and Immune Infiltration Characteristics in Ischemic Stroke

Fan

Cao

Chen

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Oxidative stress (OS) and immune inflammation play complex intersections in the pathophysiology of ischemic stroke (IS). However, a competing endogenous RNA- (ceRNA-) based mechanism linked to the intersections in IS has not been explored. We aimed to identify potential OS-related signatures and analyze immune infiltration characteristics in IS. Methods. Three datasets (GSE22255, GSE110993, and GSE140275) from the GEO database were extracted. Differentially expressed long noncoding RNAs, microRNAs, and messenger RNAs (DElncRNAs, DEmiRNAs, and DEmRNAs) between IS patients and controls were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were explored. Moreover, a triple ceRNA network was constructed to reveal transcriptional regulation mechanisms. A comprehensive strategy among least absolute shrinkage and selection operator (LASSO) regression, DEmRNAs, uprelated DEmRNAs, and OS-related genes was adopted to select the best signature. Then, we evaluated and verified the discriminant ability of the signature via receiver operating characteristic (ROC) analysis. Immune infiltration characteristics were explored via the CIBERSORT algorithm. Moreover, the best signature was verified via qPCR and western blot methods in rat brain tissues and PC12 cells. Results. 11 DEmRNAs were identified totally. Enrichment analysis showed that the DEmRNAs were primarily concentrated in MAPK-associated biological processes and immune or inflammation-involved pathways. DUSP1 was identified as the best signature with an area under the ROC curve of 73.5% ( 95 % CI = 57.02 -89.98, sensitivity = 95 % , and specificity = 60 % ) in GSE22255 and 100.0% ( 95 % CI = 100.00 -100.00, sensitivity = 100 % , and specificity = 100 % ) in GSE140275. Importantly, we also identified the AC079305/DUSP1 axis in the ceRNA network. Immune infiltration showed that resting mast cells infiltrate less in IS patients compared with controls. And DUSP1 was negatively correlated with resting mast cells ( r = − 0.703 , P < 0.01 ), whereas it was positively correlated with neutrophils ( r = 0.339 , P < 0.05 ). Both in vivo and in vitro models confirmed the upregulated expression of DUSP1 and the downregulated expression of miR-429. Conclusion. This study identified the ceRNA-based AC079305/DUSP1 axis as a promising OS-related signature for IS. Immune infiltrating cells, especially mast cells, may exert a pivotal role in IS progression. Pharmacological agents targeting signatures, their receptors, or mast cells may shed a novel light on therapeutic targets for IS.

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“…In contrast, for LV, the toll-like receptor pathway is enriched in a profile that decreases at all times compared to controls. Toll-like receptor signaling modulates critical immunomodulatory NFkB signaling and is a promising target for treating cardiovascular disease [121–123] (clinicaltrials.gov ID# NCT04734548 ). TLR signaling impacts downstream pro- or anti-inflammatory molecules, including TNFα, interleukins, interferons and TGF-β [124].…”

Section: Discussionmentioning

confidence: 99%

Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke

Carmona-Mora

Knepp

Jickling

et al. 2022

Preprint

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BackgroundAfter ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.MethodsThe transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNAseq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.ResultsUnique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils and whole blood with enrichment of interleukin signaling pathways for different timepoints and stroke etiologies. Compared to control subjects, gene expression was generally up-regulated in neutrophils and generally down- regulated in monocytes over all times for cardioembolic, large vessel and small vessel strokes. Self-Organizing Maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co- expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.ConclusionsAltogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.

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Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

Cited by 26 publications

References 243 publications

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

Investigating the AC079305/DUSP1 Axis as Oxidative Stress-Related Signatures and Immune Infiltration Characteristics in Ischemic Stroke

Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke

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