Sublytic C5b-9 Induces CCL3/4 Production and Macrophage Accumulation in Thy-1N Rats via PKC-α/p65/IRF-8 Axis

Wang, Wenbo; Qian, Baomei; Zhao, Cheng; Peng, Mingyu; Liu, Longfei; Xie, Mengxiao; Peng, Na; He, Qi; Ying, Shuai; Zhu, Yufeng; Wang, Tao; Hu, Dajun; Zhao, Dan; Zhang, Jing; Wang, Yingwei; Qiu, Wen

doi:10.7150/ijbs.69652

Cited by 8 publications

(4 citation statements)

References 58 publications

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“…According to our functional analysis, the progression of atherosclerosis related to immune infiltration is associated with the TNF and NF‐κB signalling pathways. Previous research has demonstrated that sublytic C5b‐9 triggers the production of CCL3/4 and accumulation of macrophages in Thy‐1 N rats through the PKC‐α/p65/IRF‐8 axis 28 . Building on this finding, we propose that the IRF8‐associated mechanism may play a role in the advancement of atherosclerosis following immune cell infiltration.…”

Section: Resultssupporting

confidence: 60%

“…Previous research has demonstrated that sublytic C5b-9 triggers the production of CCL3/4 and accumulation of macrophages in Thy-1 N rats through the PKC-α/p65/IRF-8 axis. 28 Building on this finding, we propose that the IRF8-associated Numerous studies have documented significant immune infiltration markers in atherosclerosis. [29][30][31] Our study used integrated bioinformatics analysis to identify the crucial gene IRF8, known for its association with immune deficiency.…”

Section: In Vitro Experiments Validated the Role Of Irf8 As An Immune...mentioning

confidence: 80%

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An integrated bioinformatics analysis reveals IRF8 as a critical biomarker for immune infiltration in atherosclerosis advance

Zhou,

Yu,

Zhang

et al. 2024

Clin Exp Pharma Physio

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Atherosclerosis, a lipid‐driven chronic inflammatory disorder, is a significant global health concern associated with high rates of morbidity and mortality, imposing a substantial societal burden. The purpose of this study is to investigate the possible molecular mechanisms of atherosclerosis and identify potential therapeutic targets. We conducted an integrated bioinformatics analysis using data from peripheral blood mononuclear cell and TISSUE databases obtained from the Gene Expression Omnibus, to identify key genes associated with the progression of atherosclerosis. Here, IRF8 was found to be a key gene in atherosclerosis patients. Silencing IRF8 with small interfering RNA reduced inflammation in endothelial cells. This suggests IRF8 is a crucial biomarker for immune infiltration in atherosclerosis advance.

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Section: Resultssupporting

confidence: 60%

Section: In Vitro Experiments Validated the Role Of Irf8 As An Immune...mentioning

confidence: 80%

An integrated bioinformatics analysis reveals IRF8 as a critical biomarker for immune infiltration in atherosclerosis advance

Zhou,

Yu,

Zhang

et al. 2024

Clin Exp Pharma Physio

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“…It functions through the activation of the NF-κB pathway, playing a role in enhancing the strength and extent of the inflammatory response. [ 39 ] VCAM-1, a member of the immunoglobulin superfamily, is upregulated in DKD and plays a crucial role in immune responses and inflammatory reactions in DKD, garnering increasing attention in DKD research. [ 40 ] These molecules act through ligand-receptor interactions and are involved in various physiological and pathological processes, including inflammation, immune responses, blood coagulation, thrombosis formation, wound healing, tumor metastasis, and dissemination.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Huaiqihuang in treatment of diabetic kidney disease based on network pharmacology, molecular docking and in vitro experiment

Wang,

Ma,

Zhang

et al. 2023

Medicine

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Background: This study aimed to investigate the active components, key targets, and potential molecular mechanisms Huaiqihuang (HQH) in the treatment of diabetic kidney disease (DKD) through network pharmacology, molecular docking, and in vitro experiments. Methods: The active components and potential targets of HQH were obtained from the TCMSP and HERB databases. The potential targets of DKD were obtained from the GeneCards, OMIM, DrugBank, and TTD databases. Protein interaction relationships were obtained from the STRING database, and a protein interaction network was constructed using Cytoscape software. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed using the Metascape database. Molecular docking was performed using AutoDock software to verify the binding between key compounds and core target genes. In vitro experiments were conducted using human renal proximal tubular epithelial cells and various methods, such as CCK8, RT-PCR, immunofluorescence, and western blot, to evaluate the effects of HQH on inflammatory factors, key targets, and pathways. Results: A total of 48 active ingredients, 168 potential targets of HQH, and 1073 potential targets of DKD were obtained. A total of 118 potential targets, 438 biological processes, and 187 signal pathways were identified for the treatment of DKD. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that HQH may exert its therapeutic effects on DKD by regulating the expression of inflammatory factors through the nuclear factor kappa B (NF-κB) signaling pathway. The molecular docking results showed that β-sitosterol and baicalein had the highest binding affinity with key targets such as AKT1, IL6, TNF, PTGS2, IL1B, and CASP3, suggesting that they may be the most effective active ingredients of HQH in the treatment of DKD. In vitro experimental results demonstrated that HQH could enhance the viability of human renal proximal tubular epithelial cells inhibited by high glucose, decrease the levels of AKT1, TNF, IL6, PTGS2, IL1B, and CASP3, reduce the expression of NF-κB-P65 (P < .01), inhibit NF-κB-p65 nuclear translocation, and decrease chemokine expression (P < .01). Conclusion: HQH may exert its therapeutic effects on DKD by inhibiting the NF-κB signaling pathway, reducing the level of pro-inflammatory cytokines, and alleviating the high glucose-induced injury of renal tubular epithelial cells.

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“…The complement components, including C1q, (18) mannose-binding lectin (MBL), (19) CFB,(20) C3a, (21) and C5a, (22) etc., can extensively interact with macrophages to regulate their polarization and functions, and previous studies demonstrate that C5b-9induced kidney injury development is mediated by macrophage. (23,24) In the present study, we elucidate the possible mechanism of the C5b-9 complex-macrophage-RTEC axis in accelerating ADPKD pathogenesis in the chronic-onset PKD mice.…”

Section: Introductionmentioning

confidence: 96%

Macrophage is vital for C5b-9-induced cyst formation and enlargement in Pkd1 -/- mice

Yang

Wang

et al. 2023

Preprint

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C5b-9 complex, the final product of complement, is overproduced during cystogenesis in the kidneys of rapid-onset mice with Pkd1 gene deficiency at postnatal day (PD)10. Compared with rapid-onset polycystic kidney disease (PKD) model, cyst enlargement is much less progressive in mice when Pkd1 gene inactivation at PD30 (chronic-onset model); however, C5b-9 infusion significantly accelerated ADPKD progression in this model. These histological data provide evidence that C5b-9 triggers renal cell apoptosis in the middle stage (PD180) and promotes cell proliferation in the late stage (PD240) in PKD mice. However, in vitro C5b-9 neither stimulated renal tubular epithelial cell (RTEC) apoptosis nor promoted RTEC proliferation, indicating that the C5b-9 indirectly affects RTECs. Furthermore, our results demonstrate that the impact of C5b-9 on cyst enlargement is significantly weakened when macrophages are depleted with liposomal clodronate (LC), suggesting that macrophages play a key role in the development of ADPKD. Moreover, C5b-9 drives bone-marrow-derived macrophages (BMDMs) to highly express TNF-α in vitro, resulting in increased cell apoptosis and contributing to cystogenesis. Additionally, the macrophages underwent M1-to-M2 transition and secreted high levels of IL-10, when cocultured with RTECs. IL-10, an M2-specific cytokine marker, remarkably stimulated RTEC proliferation. After LC-induced macrophage depletion, infusion of C5b-9-activated BMDMs significantly increased cystic phenotype in mice, proving that macrophages are vital for C5b-9-induced ADPKD.

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Sublytic C5b-9 Induces CCL3/4 Production and Macrophage Accumulation in Thy-1N Rats via PKC-α/p65/IRF-8 Axis

Cited by 8 publications

References 58 publications

An integrated bioinformatics analysis reveals IRF8 as a critical biomarker for immune infiltration in atherosclerosis advance

An integrated bioinformatics analysis reveals IRF8 as a critical biomarker for immune infiltration in atherosclerosis advance

Mechanism of Huaiqihuang in treatment of diabetic kidney disease based on network pharmacology, molecular docking and in vitro experiment

Macrophage is vital for C5b-9-induced cyst formation and enlargement in Pkd1 -/- mice

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