Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs.
Aged
Antirheumatic Agents
/ therapeutic use
Apoptosis
/ drug effects
Arthritis, Rheumatoid
/ drug therapy
Autophagy
/ drug effects
Cells, Cultured
Etanercept
/ metabolism
Female
Humans
Leukocytes, Mononuclear
/ drug effects
Male
Methotrexate
/ therapeutic use
Middle Aged
Outcome Assessment, Health Care
Tumor Necrosis Factor-alpha
/ antagonists & inhibitors
Apoptosis
Autophagy
Rheumatoid arthritis
TNF inhibitors
TNFα
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
29 01 2019
29 01 2019
Historique:
received:
06
09
2018
accepted:
09
01
2019
entrez:
31
1
2019
pubmed:
31
1
2019
medline:
17
3
2020
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30696478
doi: 10.1186/s13075-019-1818-x
pii: 10.1186/s13075-019-1818-x
pmc: PMC6352385
doi:
Substances chimiques
Antirheumatic Agents
0
Tumor Necrosis Factor-alpha
0
Etanercept
OP401G7OJC
Methotrexate
YL5FZ2Y5U1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
39Références
Immunol Rev. 2012 Sep;249(1):195-204
pubmed: 22889223
Nat Rev Rheumatol. 2016 Jan;12(1):63-8
pubmed: 26656659
FASEB J. 2012 Apr;26(4):1400-12
pubmed: 22247332
N Engl J Med. 2011 Dec 8;365(23):2205-19
pubmed: 22150039
Cytokine. 2011 Nov;56(2):140-4
pubmed: 21889357
Dev Cell. 2004 Apr;6(4):463-77
pubmed: 15068787
Arthritis Res Ther. 2012 Mar 14;14(2):R62
pubmed: 22417670
Eur J Immunol. 2016 Dec;46(12):2862-2870
pubmed: 27624289
N Engl J Med. 2001 Mar 22;344(12):907-16
pubmed: 11259725
Immunol Cell Biol. 2015 Jan;93(1):25-34
pubmed: 25287445
J Biol Chem. 2011 Feb 4;286(5):3970-80
pubmed: 20980264
Arthritis Rheum. 2010 Sep;62(9):2569-81
pubmed: 20872595
FASEB J. 2012 Nov;26(11):4722-32
pubmed: 22835828
Autoimmun Rev. 2007 Nov;7(1):35-41
pubmed: 17967723
Arthritis Res Ther. 2010;12(1):R19
pubmed: 20122151
Rheumatology (Oxford). 2010 Mar;49(3):480-9
pubmed: 20040530
Mediators Inflamm. 2017;2017:7623145
pubmed: 28255205
Clin Ter. 2013;164(5):e413-28
pubmed: 24217844
Autoimmun Rev. 2015 Jun;14(6):490-7
pubmed: 25636595
Clin Exp Immunol. 2010 Jul 1;161(1):1-9
pubmed: 20491796
Arthritis Res Ther. 2015 Dec 23;17:374
pubmed: 26702616
Autophagy. 2012 Mar;8(3):429-30
pubmed: 22361580
Arthritis Rheum. 2005 Jan;52(1):61-72
pubmed: 15641091
Nat Rev Mol Cell Biol. 2009 Jul;10(7):458-67
pubmed: 19491929
Am J Transl Res. 2017 May 15;9(5):2065-2076
pubmed: 28559961
Autophagy. 2016;12(1):1-222
pubmed: 26799652
Inflamm Res. 2013 Feb;62(2):229-37
pubmed: 23178792
Ann Rheum Dis. 2011 Oct;70(10):1857-65
pubmed: 21798884
Nat Rev Immunol. 2002 Jul;2(7):527-35
pubmed: 12094227
Immunol Cell Biol. 2006 Oct;84(5):448-54
pubmed: 16942488
Front Immunol. 2018 Jul 18;9:1577
pubmed: 30072986
Rheumatology (Oxford). 2018 Nov 1;57(11):2032-2041
pubmed: 29982776
Rheumatology (Oxford). 2016 Aug;55(8):1374-85
pubmed: 27074807
J Autoimmun. 2015 Apr;58:78-89
pubmed: 25623267