Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis

Yang, Ru; Zhang, Yingzi; Wang, Lin; Hu, Ji; Wen, Jian Guo; Xue, Leixi; Tang, Mei; Liu, Zhichun; Fu, Jinxiang

doi:10.18632/oncotarget.14331

Cited by 27 publications

(23 citation statements)

References 28 publications

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“…Autophagy has been shown to engage in a complex interplay with apoptosis, and the inhibition of autophagy reportedly induces apoptosis in several cancer cell types 48 , 49 . Moreover, autophagy inhibitors effectively inhibit the immune activation function of RA-FLS medicated by IL-6, and anti-apoptosis effects induced by IL-17 are restored by autophagy inhibition 50 , 51 . Our results showed that silibinin suppressed autophagy in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats

Zhang

Hong

et al. 2018

Sci Rep

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Silibinin, a natural polyphenolic flavonoid, possesses anti-oxidant, anti-inflammation and anti-cancer properties. The present study was designed to investigate the effects of silibinin on rheumatoid arthritis (RA) pathogenesis-related cells and collagen-induced arthritis (CIA) and further explore the potential underlying mechanisms. Our results showed that silibinin suppressed cell viability and increased the percentage of apoptotic RA-fibroblast-like synoviocytes (FLS). Furthermore, the production of inflammatory cytokines in RA-FLS and a CIA rat model was effectively inhibited by silibinin. Silibinin also induced macrophage M2 polarization in RAW264.7 cells. We further demonstrated that silibinin inhibits Th17 cell differentiation in vitro. The nuclear factor kappa B (NF-κB) pathway was suppressed in RA-FLS. In addition, Sirtuin1 (SIRT1) was decreased after silibinin treatment, and RA-FLS transfection with a short hairpin RNA (shRNA) of SIRT1 enhanced silibinin-induced apoptosis. Autophagy was markedly decreased in a dose-dependent manner following silibinin treatment. These findings indicate that silibinin inhibited inflammation by inhibiting the NF-κB pathway, and SIRT1 may participate in silibinin-induced apoptosis. Silibinin also inhibited autophagy in RA-FLS. Thus, silibinin may be a potential therapeutic agent for the treatment of RA.

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Section: Discussionmentioning

confidence: 98%

Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats

Zhang

Hong

et al. 2018

Sci Rep

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“…Further pathway examples include glucose-6-phosphate isomerase (G6PI) [ 15 ], HIF-1α [ 16 ] and TNFα [ 17 ], which mediate hypoxia-induced angiogenesis, contributed to pannus formation in RA synovia. Furthermore, plenty of activated signaling pathways promote the secretion of inflammatory factors and aggravated immune response [ 18 , 19 ]. Particularly, regulators of extracellular matrix (ECM), such as MMPs [ 20 , 21 ], which enhanced the invasiveness of FLSs, are regarded as the “killer” of joint destruction.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

et al. 2017

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Suppression of tissue inhibitor of matrix metalloproteinase (TIMP) is associated with the tumor-like invasion of fibroblast-like synoviocytes (FLSs) that occurs during rheumatoid arthritis-related cartilage destruction. Silent information regulator 2 homolog1 (SIRT1), a histone deacetylase, is widely involved in transcriptional regulation, genomic stability, metabolism and DNA repair. Recent studies suggest that SIRT1 may also impact inflammatory response and the proliferation of FLSs in rheumatoid arthritis (RA). However, it is unknown whether SIRT1 has a role in the tumor-like invasion of FLSs in rheumatoid arthritis. Herein we report that SIRT1 contributes to FLS invasion and cartilage destruction via a TIMP1-dependent mechanism. Elevated SIRT1 in RA synovia suppresses TIMP1 expression via deacetylation of TIMP1-associated histones, thereby disrupting the binding of the transcription factor specificity protein 1 (Sp1) to the TIMP1 promoter. In rats with collagen-induced arthritis, depletion of SIRT1 remarkably promoted TIMP1 expression in synovial tissues and ameliorated cartilage destruction. These results describe a new role for SIRT1 and demonstrate its potential value as a therapeutic target for rheumatoid arthritis.

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“…Autophagy is involved in the induction and suppression of inflammation and vice versa [ 6 – 8 ]. Proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 have been shown to stimulate autophagy, and autophagy also contributes to the secretion of these cytokines [ 9 – 12 ]. However, autophagy is tightly regulated in its response to inflammation, such as participating in the clearance of protein complexes (e.g., inflammasomes) through proteasomal degradation [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Association between autophagy and inflammation in patients with rheumatoid arthritis receiving biologic therapy

et al. 2018

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BackgroundIncreasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy.MethodsIn 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells.ResultsPatients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p < 0.001). p62 MFI levels in lymphocytes and granulocytes from patients with RA (17.1 and 8.6, respectively) were significantly lower than those in the corresponding cells from HC (20.2, p < 0.05; and 13.1, p < 0.001, respectively). Significantly higher levels of LC3-II protein expression in contrast to lower p62 protein levels were observed in patients with RA than in HC. The autophagosome levels in immune cells were significantly correlated with inflammatory parameters in patients with RA, and they were significantly decreased with disease remission after treatment with tumor necrosis factor-α inhibitors or interleukin-6 receptor inhibitor.ConclusionsElevated autophagy with significant correlation to inflammation suggests the involvement of autophagy in RA pathogenesis. The effectiveness of biologic therapy might be partly related to the downregulation of autophagy expression.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1763-0) contains supplementary material, which is available to authorized users.

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Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis

Cited by 27 publications

References 28 publications

Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats

Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

Association between autophagy and inflammation in patients with rheumatoid arthritis receiving biologic therapy

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