SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses

Wang, Yan; Kong, Xiangqian; Wu, Fei; Xu, Bin; Bao, Dejun; Chen, Cheng; Wei, Xiangping; Dong, Yongfei; Niu, Chaoshi

doi:10.4103/1673-5374.313049

Cited by 25 publications

(9 citation statements)

References 40 publications

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“…Speci cally, TLR upregulates TAMs via the induction of the IFNAR-STAT1 pathway [38,39], which subsequently activates the downstream expression of SOCS1 and SOCS3, resulting in the inhibitation of TLR signaling [20,24,40]. Remarkably, the SOCS family, known as classical feedback inhibitors of cytokine signal transduction, is also crucial in regulating macrophage polarization and in ammatory responses [41][42][43][44][45]. In studies conducted on APPswe/PS1dE9 mice, scientists discovered that SOCS3 suppressed microglial polarization toward the M1 phenotype by blocking IL-6 production [46].…”

Section: Discussionmentioning

confidence: 99%

Recombinant growth arrest-specific protein 6 protects the blood–brain barrier by regulating microglia polarization via the GAS6/Axl/SOCS pathway in post-stroke hemorrhagic transformation model

Liu

Zhang

et al. 2023

Preprint

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Background Blood–brain barrier (BBB) disruption is the primary cause of hemorrhagic transformation (HT) after ischemic stroke (IS). Axl is well-known as an essential innate immune regulator in macrophages. Our previous study have reported a negative association between serum Axl level and HT risk in patients after tPA thrombolysis, however, the underlying mechanism remains unclear. The present study was designed to investigate whether Axl activation could suppress BBB disruption and reduce HT in post-stroke HT model and the underlying mechanism.Methods and Results In vivo, the post-stroke HT model was established by an injection of 50% glucose and middle cerebral artery occlusion and reperfusion (MCAO/R) surgery 15min later in rats. Recombinant growth arrest-specific protein 6 (rGAS6) and R428 were injected as Axl-specific agonists and antagonists. Neurobehavioral deficits, infarction and hemorrhage volumes, brain edema, and the degree of BBB disruption were assessed. The expressions of GAS6, Axl, and suppressor of cytokine signaling (SOCS) pathway were measured. And the polarization states of microglia and the levels of inflammatory cytokines were analyzed. Our results showed that rGAS6 significantly improved neurological deficits, decreased infarct and hemorrhage volumes, alleviated brain edema and BBB disruption. Additionally, enhanced M2 polarization of microglia and a reduction in the inflammatory response were observed. Mechanism investigations suggested that rGAS6 upregulated Axl phosphorylation and the expressions of SOCS1/3. However, R428 injection abrogated the neuroprotection caused by rGAS6. The in vitro studies further supported the data of in vivo experiments, that rGAS6 treatment enhanced M2 polarization of microglia after oxygen and glucose deprivation/reoxygenation (OGD/R) stimulation via activating GAS6/Axl/SOCS1/3 pathway, which then influenced endothelial cell function.Conclusions Consequently, these data suggested that rGAS6 can protect BBB function and attenuate HT by enhancing microglial M2 polarization through activation of GAS6/Axl/SOCS signaling, and thus support rGAS6 as an effective immune modulator for the clinical prevention and treatment of IS-induced HT.

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Section: Discussionmentioning

confidence: 99%

Recombinant growth arrest-specific protein 6 protects the blood–brain barrier by regulating microglia polarization via the GAS6/Axl/SOCS pathway in post-stroke hemorrhagic transformation model

Liu

Zhang

et al. 2023

Preprint

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“…SAH is a common type of stroke and is among the leading causes of death worldwide, and dysregulated neuroinflammation has been found to exert a prominent role in brain injury following SAH [ 33 – 35 ]. This study investigated the regulatory effects of circARF3/miR-31-5p on SAH-induced BBB destruction both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of circARF3 reduces blood-brain barrier damage in rat subarachnoid hemorrhage model via miR-31-5p/MyD88/NF-κB axis

Cai¹,

Xu³

et al. 2021

Aging

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Inflammation events have been found to aggravate brain injury and blood-brain barrier (BBB) damage following subarachnoid hemorrhage (SAH). This study probed the role and mechanism of a novel circRNA, circARF3, in regulating the BBB injury in SAH rats and hypoxia-induced vascular endothelial cell (VEC) injury in vitro . Levels of circARF3 and miR-31-5p were monitored by RT-PCR. The expression of inflammatory factors IL-1β and TNF-α was verified by ELISA. In vivo SAH model was constructed in Sprague Dawley (SD) rats. The BBB integrity and cerebral edema, as well as the neurological functions of the rats were evaluated. The apoptotic neurons and microglia in brain lesions were examined by immunohistochemistry (IHC). The MyD88/NF-κB pathway was tested by Western blot. Furthermore, gain-of functional assay were constructed to explore the effects of circARF3 and miR-31-5p in primary cultured brain microvascular endothelial cell (BMEC) injury and microglial inflammation induced by oxygen and glucose deprivation (OGD). circARF3 was significantly down-regulated in plasma and CSF in SAH patients with higher Fisher stages. In the SAH rat model, overexpressing circARF3 improved BBB integrity and neurological score, decreased neuronal apoptosis and microglial activation in ipsilateral basal cortex, with declined miR-31-5p expression and MyD88-NF-κB activation. In vitro , overexpressing circARF3 attenuated OGD-mediated integrity destruction of BMECs and microglial induced neuroinflammation, while overexpressing miR-31-5p had opposite effects. Mechanistically, circARF3 sponged miR-31-5p as an endogenous competitive RNA and dampens its expression, thus inactivating MyD88-NF-κB pathway. CircARF3 attenuates BBB destruction in SAH rats by regulating the miR-31-5p-activated MyD88-NF-κB pathway.

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“…[624] and Matejas et al [625] showed that EGR1, NR4A1, SIK1, CCN1, CEBPD (CCAAT enhancer binding protein delta), SOCS2, RGS2, KL (klotho), SOCS3, MMP1, CXCR4, CCN2, FST (follistatin), OGN (osteoglycin), CTLA4, KLF4, PTGER3, HBEGF (heparin binding EGF like growth factor), CCL2, OSM (oncostatin M), ERBB4, TNFSF11, MSTN (myostatin), ADAMTS1, CALCR (calcitonin receptor), INHBB (inhibin subunit beta B), EPO (erythropoietin), IL10, CEBPB (CCAAT enhancer binding protein beta), FOXO1, DKK1, GAS1, NPHP3, FGF2, ATF3, ANGPT2, SOCS1, IL1RAP, C9ORF72, BASP1, AKR1B10, SLC22A12, ACHE (acetylcholinesterase), TREM2, SCD (stearoyl-CoA desaturase), GCK (glucokinase), FOXP3, SLC22A2, EPHB2, LPL (lipoprotein lipase), ANGPTL8, HCN2, HSPA8, MB (myoglobin), KCNJ11, GLIS2, TNFSF13, LSS (lanosterol synthase), GAS6, AGRN (agrin), ACE2, NLRP6, DPEP1, TIMP3, CHI3L1, RASAL1, FAT1, GPBAR1, TREH (trehalase), CFB (complement factor B), FNDC5, HLA-G, MMP9, C4A and LAMB2 were associated with kidney disease, but these genes might be novel targets for NAFLD. [657], SOCS3 [658], MMP1 [659], CXCR4 [660], RASD1 [661], SLC7A11 [662], OGN (osteoglycin) [341], KLF4 [663], IL1RL1 [664], CCL2 [665], EPO (erythropoietin) [666], IL10 [667], ESR2 [668], VIP (vasoactive intestinal peptide) [669], FOXC1 [670], FOXO1 [671], S100B [672], DKK1 [673], SOCS1 [674], C9ORF72 [675], CTCFL (CCCTC-binding factor like) [676], S1PR2 [677], ACHE (acetylcholinesterase) [678], TREM2 [679], EPHB2 [680], LPL (lipoprotein lipase) [681], P2RY2 [682], ACE2 [683], CHI3L1 [684], HLA-G [685] and MMP9 [686] are found in cerebrovascular diseases, but these genes might be novel targets for NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

Vastrad¹

2021

Preprint

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Non alcoholic fatty liver disease (NAFLD) is the most common metabolic disease in humans, affecting the majority of individuals. In the current investigation, we aim to identify potential key genes linked with NAFLD through bioinformatics analyses of next generation sequencing (NGS) dataset. NGS dataset of GSE135251 from the Gene Expression Omnibus (GEO) database were retrieved. Differentially expressed genes (DEGs) were obtained by DESeq2 package. g:Profiler database was further used to identify the potential gene ontology (GO) and REACTOME pathways. Protein-protein interaction (PPI) network was constructed using the Hippie interactome database. miRNet and NetworkAnalyst databases were used to establish a miRNA-hub gene regulatory network and TF-hub gene regulatory network for the hub genes. Hub genes were verified based on receiver operating characteristic curve (ROC) analysis. Totally, 951 DEGs were identified including 476 up regulated genes and 475 down regulated genes screened in NAFLD and normal control. GO showed that DEGs were significantly enhanced for signaling and regulation of biological quality. REACTOME pathway analysis revealed that DEGs were enriched in signaling by interleukins and extracellular matrix organization. ESR2, JUN, PTN, PTGER3, CEBPB, IKBKG, HSPA8, SFN, CDKN1A and E2F1 were indicated as hub genes from PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, ROC analysis revealed that ESR2, JUN, PTN, PTGER3, CEBPB, IKBKG, HSPA8, SFN, CDKN1A and E2F1 might serve as diagnostic biomarkers in NAFLD. The current investigation provided insights into the molecular mechanism of NAFLD that might be useful in further investigations.

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SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses

Cited by 25 publications

References 40 publications

Recombinant growth arrest-specific protein 6 protects the blood–brain barrier by regulating microglia polarization via the GAS6/Axl/SOCS pathway in post-stroke hemorrhagic transformation model

Recombinant growth arrest-specific protein 6 protects the blood–brain barrier by regulating microglia polarization via the GAS6/Axl/SOCS pathway in post-stroke hemorrhagic transformation model

Up-regulation of circARF3 reduces blood-brain barrier damage in rat subarachnoid hemorrhage model via miR-31-5p/MyD88/NF-κB axis

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

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