Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs
Abstract Background Autophagy 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 t...
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doaj-919249b3ead04fbfbafa7a674f1ecc732020-11-25T01:15:21ZengBMCArthritis Research & Therapy1478-63622019-01-0121111110.1186/s13075-019-1818-xReduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugsM. Vomero0V. Manganelli1C. Barbati2T. Colasanti3A. Capozzi4A. Finucci5F. R. Spinelli6F. Ceccarelli7C. Perricone8S. Truglia9S. Morrone10R. Maggio11R. Misasi12M. Bombardieri13M. Di Franco14F. Conti15M. Sorice16G. Valesini17C. Alessandri18Arthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of LondonArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeArthritis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of RomeAbstract Background Autophagy 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. Methods Peripheral 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. Results PBMCs 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. Conclusions Our 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.http://link.springer.com/article/10.1186/s13075-019-1818-xAutophagyApoptosisRheumatoid arthritisTNFαTNF inhibitors |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
M. Vomero V. Manganelli C. Barbati T. Colasanti A. Capozzi A. Finucci F. R. Spinelli F. Ceccarelli C. Perricone S. Truglia S. Morrone R. Maggio R. Misasi M. Bombardieri M. Di Franco F. Conti M. Sorice G. Valesini C. Alessandri |
spellingShingle |
M. Vomero V. Manganelli C. Barbati T. Colasanti A. Capozzi A. Finucci F. R. Spinelli F. Ceccarelli C. Perricone S. Truglia S. Morrone R. Maggio R. Misasi M. Bombardieri M. Di Franco F. Conti M. Sorice G. Valesini C. Alessandri Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs Arthritis Research & Therapy Autophagy Apoptosis Rheumatoid arthritis TNFα TNF inhibitors |
author_facet |
M. Vomero V. Manganelli C. Barbati T. Colasanti A. Capozzi A. Finucci F. R. Spinelli F. Ceccarelli C. Perricone S. Truglia S. Morrone R. Maggio R. Misasi M. Bombardieri M. Di Franco F. Conti M. Sorice G. Valesini C. Alessandri |
author_sort |
M. Vomero |
title |
Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs |
title_short |
Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs |
title_full |
Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs |
title_fullStr |
Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs |
title_full_unstemmed |
Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs |
title_sort |
reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-tnf drugs |
publisher |
BMC |
series |
Arthritis Research & Therapy |
issn |
1478-6362 |
publishDate |
2019-01-01 |
description |
Abstract Background Autophagy 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. Methods Peripheral 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. Results PBMCs 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. Conclusions Our 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. |
topic |
Autophagy Apoptosis Rheumatoid arthritis TNFα TNF inhibitors |
url |
http://link.springer.com/article/10.1186/s13075-019-1818-x |
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