Angiopoietin-2 promotes inflammatory activation of human macrophages and is essential for murine experimental arthritis.
BACKGROUND
Angiopoietin (Ang)-1 and Ang-2, and their shared receptor Tie2, are expressed in rheumatoid arthritis (RA) synovial tissue, but the cellular targets of Ang signalling and the relative contributions of Ang-1 and Ang-2 to arthritis are poorly understood.


OBJECTIVE
To determine the cellular targets of Ang signalling in RA synovial tissue, and the effects of Ang-2 neutralisation in murine collagen-induced arthritis (CIA).


METHODS
RA and psoriatic arthritis (PsA) synovial biopsies were examined for expression of Tie2 and activated phospho (p)-Tie2 by quantitative immunohistochemistry and immunofluorescent double staining. Human monocyte and macrophage Tie2 expression was determined by flow cytometry and quantitative PCR. Regulation of macrophage intracellular signalling pathways and gene expression were examined by immunoblotting and ELISA. CIA was assessed in mice treated with saline, control antibody, prednisolone or neutralising anti-Ang-2 antibody.


RESULTS
Expression of synovial Tie2 and p-Tie2 was similar in RA and PsA. Tie2 activation in RA patient synovial tissue was predominantly localised in synovial macrophages and was expressed by human macrophage. Ang-1 and Ang-2 stimulated activation of multiple intracellular signalling pathways, and cooperated with tumour necrosis factor to induce macrophage interleukin 6 and macrophage inflammatory protein 1α production. Ang-2 selectively suppressed macrophage thrombospondin-2 production. Ang-2 neutralisation significantly decreased disease severity, synovial inflammation, neo-vascularisation and joint destruction in established CIA.


CONCLUSIONS
The authors identify synovial macrophages as primary targets of Ang signalling in RA, and demonstrate that Ang-2 promotes the pro-inflammatory activation of human macrophages. Ang-2 makes requisite contributions to pathology in CIA, indicating that targeting Ang-2 may be of therapeutic benefit in the treatment of RA.
Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands.
Sarah
S
Krausz
Samuel
S
Garcia
Carmen A
CA
Ambarus
Daphne
D
de Launay
Martyn
M
Foster
Brian
B
Naiman
William
W
Iverson
Jane R
JR
Connor
Matthew A
MA
Sleeman
Anthony J
AJ
Coyle
Jorg
J
Hamann
Dominique
D
Baeten
Paul P
PP
Tak
Kris A
KA
Reedquist
D042683:Angiopoietin-1 / Q000378:metabolism / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015535:Arthritis, Psoriatic / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D054405:Chemokine CCL3 / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D042787:Receptor, TIE-2; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D019699:Thrombospondins / Q000096:biosynthesis; D000099262:Thrombospondin 2
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D019138:Antibodies, Blocking; D054405:Chemokine CCL3; D015850:Interleukin-6; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D019699:Thrombospondins; D000099262:Thrombospondin 2; C079086:Tek protein, mouse