Autophagy induces protein carbamylation in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Manganelli, Valeria; Recalchi, Serena; Capozzi, Antonella; Riitano, Gloria; Mattei, Vincenzo; Longo, Agostina; Franco, Manuela Di; Alessandri, Cristiano; Bombardieri, Michèle; Valesini, Guido; Misasi, Roberta; Garofalo, Tina; Sorice, Maurizio

doi:10.1093/rheumatology/key174

Cited by 15 publications

(9 citation statements)

References 44 publications

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“…Autophagy actively participates in protein citrullination and carbamylation by substrates for the formation of autoantibodies [9, 10]. In fact, stimuli that induce autophagy were able to activate PAD4 enzyme in FLS from RA patients [9].…”

Section: Introductionmentioning

confidence: 99%

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Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs

et al. 2019

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BackgroundAutophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate.MethodsPeripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA.ResultsPBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins.ConclusionsOur results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-019-1818-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

“…Also, ex vivo analysis in monocytes from early-naïve RA patients revealed an interesting direct correlation between autophagy levels and anti-cyclic citrullinated peptide (anti-CCP) titer. Recently, the same experimental condition was used to demonstrate that also carbamylation process was related to autophagy activation [10].…”

Section: Introductionmentioning

confidence: 99%

Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs

et al. 2019

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“…In addition, studies have shown that autophagy may be involved in the carbamylation of FLS proteins, a non-enzymatic posttranslational modification mechanism, which results in their accumulation and subsequent participation in the pathogenesis of RA. However, the specific mechanism underlying this phenomenon is not yet clear (119).…”

Section: Autophagy Increases Auto-antigen Presentation By Antigen-presenting Cellsmentioning

confidence: 99%

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

et al. 2021

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Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.

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“…Smoking may also induce carbamylation [ 232 ], and mononuclear cells of treatment-naïve RA patients show a correlation between autophagy and the level of carbamylation [ 233 ]. The carbamylated form of hemoglobin and low-density lipoprotein (LDL), detectable by laboratory tests, is correlated with acute or chronic renal failure and atherosclerosis, respectively [ 234 , 235 , 236 , 237 , 238 ].…”

Section: Carbamylation In Ramentioning

confidence: 99%

Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation

Kwon

2021

IJMS

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Rheumatoid arthritis (RA) is caused by prolonged periodic interactions between genetic, environmental, and immunologic factors. Posttranslational modifications (PTMs) such as citrullination, carbamylation, and acetylation are correlated with the pathogenesis of RA. PTM and cell death mechanisms such as apoptosis, autophagy, NETosis, leukotoxic hypercitrullination (LTH), and necrosis are related to each other and induce autoantigenicity. Certain microbial infections, such as those caused by Porphyromonasgingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella copri, can induce autoantigens in RA. Anti-modified protein antibodies (AMPA) containing anti-citrullinated protein/peptide antibodies (ACPAs), anti-carbamylated protein (anti-CarP) antibodies, and anti-acetylated protein antibodies (AAPAs) play a role in pathogenesis as well as in prediction, diagnosis, and prognosis. Interestingly, smoking is correlated with both PTMs and AMPAs in the development of RA. However, there is lack of evidence that smoking induces the generation of AMPAs.

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Autophagy induces protein carbamylation in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Cited by 15 publications

References 44 publications

Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs

Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation

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