Interleukin-36 family dysregulation drives joint inflammation and therapy response in psoriatic arthritis

被引:40
作者
Boutet, Marie-Astrid [1 ,2 ]
Nerviani, Alessandra [1 ,2 ]
Lliso-Ribera, Gloria [1 ,2 ]
Lucchesi, Davide [1 ,2 ]
Prediletto, Edoardo [1 ,2 ]
Ghirardi, Giulia Maria [1 ,2 ]
Goldmann, Katriona [1 ,2 ]
Lewis, Myles [1 ,2 ]
Pitzalis, Costantino [1 ,2 ]
机构
[1] Queen Mary Univ London, Ctr Expt Med & Rheumatol, William Harvey Res Inst, London, England
[2] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England
基金
英国医学研究理事会;
关键词
psoriatic arthritis; rheumatoid arthritis; synovitis; inflammation; cytokines; early arthritis; interleukin-36; RHEUMATOID-ARTHRITIS; ANTAGONIST IL-36RA; RECEPTOR; IL-1F8; CELLS; SKIN;
D O I
10.1093/rheumatology/kez358
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objectives. IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naive PsA, and for comparison RA patients, pre- and post-DMARDs therapy. Methods. Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naive PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes. Results. PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36 alpha was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts. Conclusion. The impaired balance between IL-36 agonists-antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.
引用
收藏
页码:828 / 838
页数:11
相关论文
共 39 条
[11]   Blockade of IL-36 Receptor Signaling Does Not Prevent from TNF-Induced Arthritis [J].
Derer, Anja ;
Groetsch, Bettina ;
Harre, Ulrike ;
Boehm, Christina ;
Towne, Jennifer ;
Schett, Georg ;
Frey, Silke ;
Hueber, Axel J. .
PLOS ONE, 2014, 9 (08)
[12]   INFLAMMATION IL-36 has proinflammatory effects in skin but not in joints [J].
Dietrich, Damien ;
Gabay, Cem .
NATURE REVIEWS RHEUMATOLOGY, 2014, 10 (11) :639-640
[13]   Mutation Analysis of the IL36RN Gene in 14 Japanese Patients with Generalized Pustular Psoriasis [J].
Farooq, Muhammad ;
Nakai, Hiroyuki ;
Fujimoto, Atsushi ;
Fujikawa, Hiroki ;
Matsuyama, Asako ;
Kariya, Naoyuki ;
Aizawa, Atsuko ;
Fujiwara, Hiroshi ;
Ito, Masaaki ;
Shimomura, Yutaka .
HUMAN MUTATION, 2013, 34 (01) :176-183
[14]   IL-36 Promotes Myeloid Cell Infiltration, Activation, and Inflammatory Activity in Skin [J].
Foster, Alexander M. ;
Baliwag, Jaymie ;
Chen, Cynthia S. ;
Guzman, Andrew M. ;
Stoll, Stefan W. ;
Gudjonsson, Johann E. ;
Ward, Nicole L. ;
Johnston, Andrew .
JOURNAL OF IMMUNOLOGY, 2014, 192 (12) :6053-6061
[15]   The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium [J].
Frey, Silke ;
Derer, Anja ;
Messbacher, Maria-Elena ;
Baeten, Dominique L. P. ;
Bugatti, Serena ;
Montecucco, Carlomaurizio ;
Schett, Georg ;
Hueber, Axel J. .
ANNALS OF THE RHEUMATIC DISEASES, 2013, 72 (09) :1569-1574
[16]   Generation and functional characterization of anti-human and anti-mouse IL-36R antagonist monoclonal antibodies [J].
Ganesan, Rajkumar ;
Raymond, Ernest L. ;
Mennerich, Detlev ;
Woska, Joseph R., Jr. ;
Caviness, Gary ;
Grimaldi, Christine ;
Ahlberg, Jennifer ;
Perez, Rocio ;
Roberts, Simon ;
Yang, Danlin ;
Jerath, Kavita ;
Truncali, Kristopher ;
Frego, Lee ;
Sepulveda, Eliud ;
Gupta, Priyanka ;
Brown, Su-Ellen ;
Howellz, Michael D. ;
Canada, Keith A. ;
Kroe-Barrett, Rachel ;
Fine, Jay S. ;
Singh, Sanjaya ;
Mbow, M. Lamine .
MABS, 2017, 9 (07) :1143-1154
[17]   The enigmatic role of IL-38 in inflammatory diseases [J].
Garraud, Thomas ;
Harel, Mathilde ;
Boutet, Marie-Astrid ;
Le Goff, Benoit ;
Blanchard, Frederic .
CYTOKINE & GROWTH FACTOR REVIEWS, 2018, 39 :26-35
[18]   Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines [J].
Henry, Conor M. ;
Sullivan, Graeme P. ;
Clancy, Danielle M. ;
Afonina, Inna S. ;
Kulms, Dagmar ;
Martin, Seamus J. .
CELL REPORTS, 2016, 14 (04) :708-722
[19]   Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium [J].
Humby, Frances ;
Bombardieri, Michele ;
Manzo, Antonio ;
Kelly, Stephen ;
Blades, Mark C. ;
Kirkham, Bruce ;
Spencer, Jo ;
Pitzalis, Costantino .
PLOS MEDICINE, 2009, 6 (01) :59-75
[20]   Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients [J].
Kelly, S. ;
Humby, F. ;
Filer, A. ;
Ng, N. ;
Di Cicco, M. ;
Hands, R. E. ;
Rocher, V. ;
Bombardieri, M. ;
D'Agostino, M. A. ;
McInnes, I. B. ;
Buckley, C. D. ;
Taylor, P. C. ;
Pitzalis, C. .
ANNALS OF THE RHEUMATIC DISEASES, 2015, 74 (03) :611-617