TY - JOUR
T1 - PEGylated TRAIL ameliorates experimental inflammatory arthritis by regulation of Th17 cells and regulatory T cells
AU - Park, Jong Sung
AU - Oh, Yumin
AU - Park, Ogyi
AU - Foss, Catherine A.
AU - Lim, Sung Mook
AU - Jo, Dong Gyu
AU - Na, Dong Hee
AU - Pomper, Martin G.
AU - Lee, Kang Choon
AU - Lee, Seulki
N1 - Funding Information:
This study was supported by grants from the US Department of Defense ( CA130460 to S.L.) and the National Research Foundation of Korea ( NRF-2016R1A2B4006914 to K.C.L.) and the Donald B. & Dorothy L. Stabler Foundation and the Jerome L. Greene Fund (M.G.P.).
Publisher Copyright:
© 2017
PY - 2017/12/10
Y1 - 2017/12/10
N2 - TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand that can induce apoptosis in cells expressing its cognate death receptors (DRs). Previously, we demonstrated the therapeutic potential of recombinant human TRAIL in experimental rheumatoid arthritis (RA) models. However, the mechanisms of how DR-mediated apoptosis elicits these actions is not known. Here, we show that systemically administering a potent, long-acting PEGylated TRAIL (TRAILPEG) is profoundly anti-rheumatic against two complementary experimental RA mouse models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA), via targeting IL-17 secreting Th17 cells and regulatory T cells (Treg). Systemic administration of TRAILPEG after disease onset ameliorated the severity of inflammatory arthritis including arthritis indices, paw thickness, cartilage damage and neutrophil infiltration in both CIA and CAIA models. Additionally, the levels of inflammatory molecules (p-p65, ICAM-1, Cox-2, MMP3, and iNOS), pro-inflammatory cytokines (TNF-α IL-1β IFN-γ IL-6, IL-17) and accumulation of activated macrophages were significantly reduced after the TRAILPEG treatment. Importantly, TRAILPEG decreased the number of pro-inflammatory Th17 cells in inflamed arthritic joints through TRAIL-induced apoptosis while increasing anti-inflammatory Treg population in vivo. These results suggest that TRAILPEG ameliorates autoimmunity by targeting the Th 17-Tregs axis, making it a promising candidate drug for the treatment of RA.
AB - TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand that can induce apoptosis in cells expressing its cognate death receptors (DRs). Previously, we demonstrated the therapeutic potential of recombinant human TRAIL in experimental rheumatoid arthritis (RA) models. However, the mechanisms of how DR-mediated apoptosis elicits these actions is not known. Here, we show that systemically administering a potent, long-acting PEGylated TRAIL (TRAILPEG) is profoundly anti-rheumatic against two complementary experimental RA mouse models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA), via targeting IL-17 secreting Th17 cells and regulatory T cells (Treg). Systemic administration of TRAILPEG after disease onset ameliorated the severity of inflammatory arthritis including arthritis indices, paw thickness, cartilage damage and neutrophil infiltration in both CIA and CAIA models. Additionally, the levels of inflammatory molecules (p-p65, ICAM-1, Cox-2, MMP3, and iNOS), pro-inflammatory cytokines (TNF-α IL-1β IFN-γ IL-6, IL-17) and accumulation of activated macrophages were significantly reduced after the TRAILPEG treatment. Importantly, TRAILPEG decreased the number of pro-inflammatory Th17 cells in inflamed arthritic joints through TRAIL-induced apoptosis while increasing anti-inflammatory Treg population in vivo. These results suggest that TRAILPEG ameliorates autoimmunity by targeting the Th 17-Tregs axis, making it a promising candidate drug for the treatment of RA.
KW - Apoptosis
KW - Autoimmune diseases
KW - Inflammation
KW - Rheumatoid arthritis
KW - TH17-Treg
KW - TRAIL
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UR - http://www.scopus.com/inward/citedby.url?scp=85031732991&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2017.10.004
DO - 10.1016/j.jconrel.2017.10.004
M3 - Article
C2 - 29017854
AN - SCOPUS:85031732991
SN - 0168-3659
VL - 267
SP - 163
EP - 171
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -