TY - JOUR
T1 - Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients
AU - Kabala, Pawel A.
AU - Malvar-Fernández, Beatriz
AU - Lopes, Ana P.
AU - Carvalheiro, Tiago
AU - Hartgring, Sarita A. Y.
AU - Tang, Man Wai
AU - Conde, Carmen
AU - Baeten, Dominique L.
AU - Sleeman, Matthew
AU - Tak, Paul P.
AU - Connor, Jane
AU - Radstake, Timothy R.
AU - Reedquist, Kris A.
AU - García, Samuel
N1 - Funding Information: Funding: This research was supported in part by the Dutch Arthritis Association Project Grants (NR 04-1-301 and NR 09-1-405) to K.A.R. Funding Information: S.G. was supported by the Anxeles Alvariño postdoctoral programme (I + D + I Xunta de Galicia) and the European Social Fund (ESF). T.C. was supported by a Grant from the Portuguese national funding agency for science, research and technology: Fundac¸ ão para a Ciência e a Tecnologia (SFRH/BD/93526/2013). D.L.B. is supported by a Vidi grant from the Dutch Scientific Organization. Publisher Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2
Y1 - 2020/2
N2 - OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases.
AB - OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases.
KW - Angiopoietins
KW - Inflammation
KW - Macrophages
KW - Psoriatic arthritis
KW - Rheumatoid arthritis
KW - Serum transfer-induced arthritis
KW - Synovial tissue explants
KW - Tie2
UR - http://www.scopus.com/inward/record.url?scp=85078551613&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/rheumatology/kez315
DO - https://doi.org/10.1093/rheumatology/kez315
M3 - Article
C2 - 31377797
SN - 1462-0324
VL - 59
SP - 426
EP - 438
JO - Rheumatology (Oxford, England)
JF - Rheumatology (Oxford, England)
IS - 2
ER -