CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Xu, Bing; Li, Jian; Wu, Changsun; Liu, Chunyan; Yan, Xinfeng; Chang, Xiaotian

doi:10.3899/jrheum.170170

Cited by 8 publications

(11 citation statements)

References 11 publications

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“…TXNDC5 contributes to abnormal RA FLS proliferation, migration and IL-6 production by inhibiting IGFBP1 expression 34 . Downregulation of TXNDC5 could contribute to RA FLS antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL 35 . Further, TXNDC5 synergizes with heat shock cognate 70 protein (HSC70) to exacerbate the inflammatory phenotype of RA FLS through NF-κB signaling 36 .…”

Section: Discussionmentioning

confidence: 99%

Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

Seny

Bianchi

Baiwir

et al. 2020

Sci Rep

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2D-nano-UPLC-ESI-Q-Orbitrap 2 Dimensional-nano-ultra performance liquid chromatography-electrospay ionization-Q-Orbitrap CALR Calreticulin CPPA Chronic pyrophosphate arthropathy CRP C-reactive protein DAMPS Damage-associated molecular patterns ER Endoplasmic reticulum ERAD ER-associated degradation FLS Fibroblast-like synoviocytes GRP78 Glucose-regulated protein 78 kDa LC-MS/MS Liquid chromatography-tandem mass spectrometry LFQ Label free quantification MRI Magnetic resonance imaging OA Osteoarthritis PMN Polymorphonuclear cells PSM Peptide spectrum match RA Rheumatoid arthritis TLR Toll-like receptors TXNDC5 Thioredoxin domain-containing protein 5 UPR Unfolded protein response US Ultrasonography Osteoarthritis (OA) was for long considered as a degenerative cartilage disease for which synovitis was only visualized in the late stages and considered as secondary to mechanic aggression of bone and cartilage degradation. However, several observations demonstrated that synovitis could appear even in the early stages of OA. Synovium can also acquire an "inflammatory" phenotype in OA with similar characteristics than those observed in rheumatoid arthritis (RA) for which synovitis is the hallmark: [i.e. synovial lining and villous hyperplasia, infiltration by macrophages and lymphocytes, neo-angiogenesis and fibrosis] 1,2. Using magnetic resonance imaging (MRI), Roemer et al. noted a synovitis in 96.3% of knee joints with effusion and in 70% of knee joint without effusion 3. We previously published by using ultrasonography (US) examination that 53.7% (322/600) of patients with painful knee OA had no sign of inflammation whereas 2.7% (16/600) had synovitis alone, 14.2% (85/600) had both synovitis and effusion and 29.5% (177/600) had joint effusion alone 4. US knee synovitis and US joint effusion were significantly associated with a more severe radiological grade (Kellgren-Lawrence grade ≥ 3) and a moderate-important joint effusion at clinical examination 4. Further, several other studies have confirmed the correlation between synovitis area observed by MRI and specific histologic features of synovitis 5. Two major pathways at least can explain the development of synovitis: activation of toll-like receptors (TLR) and activation of the complement cascade 1. Endogenous "damage-associated molecular patterns" (DAMPS) can activate the innate immune response through TLRs recognition promoting pro-inflammatory mediators secretion 6,7. Activation of the complement cascade induces complement deposits sparsely found in the synovium of OA patients. Deposits of synovial complement components were only observed during acute OA flare but not during chronic OA 8. More recently, proteomic analyses of OA synovial fluids 9,10 and transcriptomic studies of OA synovial membranes 10 confirmed the expression and activation of complement in joints 11. Proteomic analysis of synovial tissue was rarely performed 12,13 and none was compared to the histological pattern of synovium. In this work, we compared protein profiles generated by a proteomic s...

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Section: Discussionmentioning

confidence: 99%

Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

Seny

Bianchi

Baiwir

et al. 2020

Sci Rep

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“…Downregulation of TXNDC5 could contribute to RA FLS antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (33). Further, TXNDC5 synergizes with heat shock cognate 70 protein (HSC70) to exacerbate the inflammatory phenotype of RA FLS through NF-κB signaling (34).…”

Section: Discussionmentioning

confidence: 99%

Proteins involved in the endoplasmic reticulum stress are key players in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological score

Seny

Bianchi

Baiwir

et al. 2020

Preprint

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Background: It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist among the three pathologies presenting an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA).Methods: Synovial biopsies of OA (n=9), CPPA (n=7) and RA (n=8) patients were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score.Results: Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p<0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only one (complement C1q subcomponent, subunit B and C) was weakly correlated with the histological score.Conclusions: This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.

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“…As for CXCL10, markedly elevated protein levels were also detected in PBOV1 -overexpressed THP-1 supernatants. The pro-inflammatory chemokine CXCL10 has been reported to attract activated macrophages, T cells, and NK cells to the site of inflammation and is upregulated in autoimmune diseases, including RA [ 38 , 39 , 40 , 41 , 42 ]. It is suggested that CXCL10 increases the migration of inflammatory cells via CXCR3-mediated ERK activation and stimulates the production of osteoclastogenic cytokines in CD4+ T cells, resulting in bone destruction in RA [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

lncRNA NTT/PBOV1 Axis Promotes Monocyte Differentiation and Is Elevated in Rheumatoid Arthritis

Yang

Yen

et al. 2018

IJMS

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Monocytes/macrophages are important in orchestrating inflammatory responses. However, knowledge of the long noncoding RNA (lncRNA) regulation of monocytic cell differentiation and diseases remains limited. We aimed to elucidate the role of the 17 kb lncRNA noncoding transcript in T cells (NTT) in monocyte functions. Knockdown and chromatin immunoprecipitation (ChIP) assays in THP-1 cells (human monocytic leukemia cell line) revealed that NTT is regulated by the monocyte key transcription factor C/EBPβ and that it binds to the promoter of nearby gene PBOV1 via hnRNP-U. Overexpression of PBOV1 in THP-1 cells resulted in cell cycle G1 arrest, differentiation into macrophages, a marked increase in IL-10 and CXCL10 mRNA levels, and upregulation of the costimulatory molecules. In contrast to the downregulated NTT observed in lipopolysaccharide (LPS)-treated THP-1 cells, the C/EBPβ/NTT/PBOV1 axis was found to be hyperactivated in peripheral blood mononuclear cells (PBMCs) of first-time diagnosed untreated early rheumatoid arthritis (RA) patients, and their gene expression levels decreased markedly after treatment. Higher initial C/EBPβ/NTT/PBOV1 expression levels were associated with a trend of higher disease activity DAS28 scores. In conclusion, our study suggests that the lncRNA NTT is a regulator of inflammation in monocytes, and its activation participates in monocyte/macrophage differentiation and the pathogenesis of RA.

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CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Abstract: Downregulation of TXNDC5 could contribute to RASF antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).

Cited by 8 publications

References 11 publications

Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

Proteins involved in the endoplasmic reticulum stress are key players in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological score

lncRNA NTT/PBOV1 Axis Promotes Monocyte Differentiation and Is Elevated in Rheumatoid Arthritis

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