Semaphorin 4A acts in a feed-forward loop with NF-κB pathway to exacerbate catabolic effect of IL-1β on chondrocytes

Zhang, Hua; Wei, Qiushi; Xiang, Xiaobing; Zhou, Bengen; Chen, Jianfa; Li, Jie; Li, Qihuo; Xiong, Hao; Liu, Fuyifei

doi:10.1016/j.intimp.2019.01.006

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…Zhou et al found that the Rac1/AKT signaling pathway played an important regulatory role in inflammatory response [26]. NF-κB has attracted widespread attention because of its key role in regulating inflammation [27]. To confirm that the therapeutic effect of DEX on SD is related to the Rac1/AKT signaling pathway, the changes in protein expressions of Rac1/AKT/NF-κB and the entry of NF-κB into the nucleus in the hippocampus were detected in this study.…”

Section: Discussionmentioning

confidence: 99%

Effects of dexmedetomidine on postoperative cognitive function of sleep deprivation rats based on changes in inflammatory response

et al. 2021

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We aimed to assess the effects of dexmedetomidine (DEX) on postoperative cognitive function of sleep deprivation (SD) rats based on changes in inflammatory response. Male rats were randomly divided into blank control (C), SD, DEX, and SD+DEX groups. The SD model was established through intraperitoneal injection of DEX. The escape latency was detected through Morris water maze test daily, and the mechanical withdrawal threshold and thermal withdrawal latency were detected for 8 d. The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in hippocampus homogenate were determined, and the morphological changes in neurons were detected through Nissl staining. The concentration of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 in the hippocampus was detected by enzyme-linked immunosorbent assay, and the Rac1/protein kinase B (AKT)/nuclear factor-κB (NF-κB) expressions were detected by Western blotting. The changes in immunofluorescence localization of NF-κB were observed by confocal microscopy. Compared with SD group, the escape latency was shortened, original platform-crossing times increased, MDA content declined, SOD activity rose, neurons were arranged orderly and number of Nissl bodies increased in the hippocampal CA1 region, levels of IL-1β, TNFα, and IL-6 in the hippocampus decreased, Rac1/AKT/NF-κB expressions were down-regulated, and proportion of NF-κB entering the nucleus declined in SD+DEX group (P < 0.05). DEX can effectively alleviate postoperative hippocampal inflammation and improve cognitive function of SD rats. The ability of DEX to relieve oxidative stress of hippocampal neurons, restore damaged cells, and reduce hippocampal inflammation in SD rats may be related to the Rac1/AKT/NF-κB pathway.

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Section: Discussionmentioning

confidence: 99%

Effects of dexmedetomidine on postoperative cognitive function of sleep deprivation rats based on changes in inflammatory response

et al. 2021

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“…Presently, we cannot totally exclude the possibility that gp96 indirectly controls Treg expansion and function by interaction with other immune cell types, such as pDCs ( Kinner-Bibeau et al., 2017 ). It is possible that NF-κB activation in Tregs by gp96 may upregulate Sema4a that facilitates its interaction with pDC ( Zhang et al., 2019 ). In addition, more studies are needed to elucidate the role of different TLRs in gp96-induced Foxp3 expression, although our primary data showed that TLR2 may play an essential role in this process.…”

Section: Discussionmentioning

confidence: 99%

Induction of Foxp3 and activation of Tregs by HSP gp96 for treatment of autoimmune diseases

Liu

Xie

et al. 2021

iScience

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Summary Upregulation and stabilization of Foxp3 expression in Tregs are essential for regulating Treg function and immune homeostasis. In this study, gp96 immunization showed obvious therapeutic effects in a Lyn –/– mouse model of systemic lupus erythematosus. Moreover, gp96 alleviated the initiation and progression of MOG-induced experimental autoimmune encephalomyelitis. Immunization of gp96 increased Treg frequency, expansion, and suppressive function. Gene expression profiling identified the NF-κB family member p65 and c-Rel as the key transcription factors for enhanced Foxp3 expression in Treg by gp96. Mutant gp96 within its Toll-like receptor (TLR) binding domain, TLR2 knockout mice, and mice with cell-specific deletion of MyD88, were used to demonstrate that gp96 activated Tregs and induced Foxp3 expression via a TLR2-MyD88-mediated NF-κB signaling pathway. Taken together, these results show that gp96 immunization restricted antibody-induced and Th-induced autoimmune diseases by integrating Treg expansion and activation, indicating its potential clinical usefulness against autoimmune diseases.

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“…The matrix degradation gene, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-5), and the chondrocyte hypertrophy marker, type X collagen (COLX) are also upregulated by Rac1 in chondrocytes, accelerating OA progression ( Zhu et al., 2015 ). The Rac1/Akt pathway stimulates the phosphorylation of inhibitor of nuclear factor kappa B (IκBα) and degradation, which further enhances NF-κB activity to stimulate the expression of proinflammatory mediators, including nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX2), as well as the collagen degradation proteins, MMP3 and MMP13 ( Zhang et al., 2019 ). The RhoA/ROCK pathway also enhances cartilage damage by collagen degradation ( Appleton et al., 2010 ).…”

Section: Rho Gtpases In Rheumatic Diseasesmentioning

confidence: 99%

“…(2019) Rac1 aggravates cartilage degradation in OA via the activation of Akt and NF-κB pathway. Rac1–Akt–IκBα–NF-κB–MMP3/13, NOS2, COX2 in vivo Knock-down (siRNA) Zhang et al. (2019) RhoA RhoA/ROCK pathway inhibition reduces the degradation of collagen.…”

Section: Targeted Therapymentioning

confidence: 99%

Rho GTPase signaling in rheumatic diseases

et al. 2022

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Summary Rho guanosine triphosphatase (GTPases), as molecular switches, have been identified to be dysregulated and involved in the pathogenesis of various rheumatic diseases, mainly including rheumatoid arthritis, osteoarthritis, systemic sclerosis, and systemic lupus erythematosus. Downstream pathways involving multiple types of cells, such as fibroblasts, chondrocytes, synoviocytes, and immunocytes are mediated by activated Rho GTPases to promote pathogenesis. Targeted therapy via inhibitors of Rho GTPases has been implicated in the treatment of rheumatic diseases, demonstrating promising effects. In this review, the effects of Rho GTPases in the pathogenesis of rheumatic diseases are summarized, and the Rho GTPase-mediated pathways are elucidated. Therapeutic strategies using Rho GTPase inhibitors in rheumatic diseases are also discussed to provide insights for further exploration of targeted therapy in preclinical studies and clinical practice. Future directions on studies of Rho GTPases in rheumatic diseases based on current understandings are provided.

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Semaphorin 4A acts in a feed-forward loop with NF-κB pathway to exacerbate catabolic effect of IL-1β on chondrocytes

Cited by 9 publications

References 34 publications

Effects of dexmedetomidine on postoperative cognitive function of sleep deprivation rats based on changes in inflammatory response

Effects of dexmedetomidine on postoperative cognitive function of sleep deprivation rats based on changes in inflammatory response

Induction of Foxp3 and activation of Tregs by HSP gp96 for treatment of autoimmune diseases

Rho GTPase signaling in rheumatic diseases

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