Open AccessDeath Receptor 5–Targeted Depletion of Interleukin‐23–Producing Macrophages, Th17, and Th1/17 Associated With Defective Tyrosine Phosphatase in Mice and Patients With Rheumatoid Arthritis
Author(s) -
Li Jun,
Yang PingAr,
Wu Qi,
Li Hao,
Ding Yanna,
Hsu HuiChen,
Spalding David M.,
Mountz John D.
Publication year - 2013
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.38057
Subject(s) - immunology , inflammation , protein tyrosine phosphatase , granulocyte macrophage colony stimulating factor , macrophage , irf5 , interleukin 17 , arthritis , medicine , autoantibody , cytokine , biology , receptor , antibody , interferon regulatory factors , immune system , innate immune system , in vitro , biochemistry
Objective Bidirectional interactions between granulocyte–macrophage colony‐stimulating factor–positive (GM‐CSF+) T cells and interferon regulatory factor 5–positive (IRF‐5+) macrophages play a major role in autoimmunity. In the absence of SH2 domain–containing phosphatase 1 (SHP‐1), GM‐CSF–stimulated cells are resistant to death receptor (DR)–mediated apoptosis. The objective of this study was to determine whether TRA‐8, an anti–DR5 agonistic antibody, can eliminate inflammatory macrophages and CD4 T cells in the SHP‐1–deficient condition. Methods Ubiquitous Cre (Ubc.Cre) human/mouse‐chimeric DR5–transgenic mice were crossed with viable SHP‐1–defective motheaten ( me v / me v ) mice. TRA‐8 was administered weekly for up to 4 weeks. The clinical scores, histopathologic severity, and macrophage and CD4 T cell phenotypes were evaluated. The role of TRA‐8 in depleting inflammatory macrophages and CD4 T cells was also evaluated, using synovial fluid obtained from patients with rheumatoid arthritis (RA). Results The levels of inflammatory macrophages (interleukin‐23–positive [IL‐23+] IRF‐5+) and CD4 T cells (IL‐17+ GM‐CSF+) were elevated in me v / me v mice. In DR5‐transgenic me v / me v mice, DR5 expression was up‐regulated in these 2 cell populations. TRA‐8 treatment depleted these cell populations and resulted in a significant reduction in inflammation and in the titers of autoantibodies. In synovial cells from patients with RA, the expression of IRF5 and DR5 was negatively correlated with the expression of PTPN6 . TRA‐8, but not TRAIL, suppressed RA inflammatory macrophages and Th17 cells under conditions in which the expression of SHP‐1 is low. Conclusion In contrast to TRAIL, which lacks the capability to counteract the survival signal in the absence of SHP‐1, TRA‐8 eliminated both IRF‐5+ IL‐23+ M1 macrophages and pathogenic GM‐CSF+ IL‐17+ CD4 T cells in a SHP‐1–independent manner. The results of the current study suggest that TRA‐8 can deplete inflammatory cell populations that result from a hyperactive GM‐CSF/IRF‐5 axis.