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

Abstract

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.

Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis

“…These citrullinated proteins are known targets for ACPAs, and the level of autophagy markers is well correlated with the titer of ACPAs [100]. Such a notion is also supported by the synchronized reduction of autophagy and levels of citrullinated proteins in patients with RA upon etanercept treatment [103]. In addition, although it is still unclear whether NETosis creates pathogenic citrullination or merely redistributes an existing citrullinome, the release of citrullinated autoantigens extracellularly has been demonstrated to trigger ACPA-associated experimental arthritis [48,99,104].…”

PI3K abrogation using pan PI3K inhibitor BKM120 give rise to a weighty anti-cancer effect on AML-derived KG-1 cells by inducing apoptosis and G2/M arrest

“…Our results showed that the amounts of annexin-V cells were elevated in comparison with the control group, which is in agreement with the augmented cells in the sub-G1 phase ( Figure 4A ). Numerous studies have demonstrated that the alteration of the autophagy system may act as an important contributory mechanism affecting the extent of cell death induced by anticancer agents in malignant cells [ 19 , 20 , 21 ]. To investigate the contributory role of autophagy in BKM120 cytotoxicity, the effect of CQ, a well-known autophagy inhibitor, was examined as both a single agent and in combination with the PI3K inhibitor.…”

Autophagy Modulation in Lymphocytes From COVID-19 Patients: New Therapeutic Target in SARS-COV-2 Infection

“…We previously demonstrated that TNF-α activated autophagy in peripheral lymphocytes from RA patients. The treatment with drugs that block this cytokine, such as etanercept, reduced in vitro the autophagy marker LC3-II (Vomero et al, 2019). Only patients that responded to anti-TNF therapy showed a significant reduction in autophagy levels.…”

“…We identified the α-synuclein as a new autophagy marker in T lymphocytes (Alessandri et al, 2012;Colasanti et al, 2014). We described that not only TNFα induced autophagy in peripheral blood mononuclear cells from rheumatoid arthritis (RA) patients, but also that the balance between autophagy and apoptosis was involved in response to therapy in RA patients treated with TNF inhibitors (Vomero et al, 2019).…”