PEGylated TRAIL ameliorates experimental inflammatory arthritis by regulation of Th17 cells and regulatory T cells.

Abstract

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.

• Authors: Jong-Sung Park, Yumin Oh, Ogyi Park, Catherine A Foss, Sung Mook Lim, Dong-Gyu Jo, Dong Hee Na, Martin G Pomper, Kang Choon Lee, Seulki Lee
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 267 Pg. 163-171 (Dec 10 2017) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 29017854 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• Cytokines
• RNA, Messenger
• TNF-Related Apoptosis-Inducing Ligand
• Polyethylene Glycols

Topics

• Animals
• Arthritis, Experimental (drug therapy, genetics, immunology, pathology)
• Cytokines (blood, genetics, immunology)
• Knee Joint (drug effects, immunology, pathology)
• Male
• Mice, Inbred DBA
• Polyethylene Glycols (administration & dosage, chemistry, pharmacology, therapeutic use)
• RNA, Messenger (metabolism)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, chemistry, pharmacology, therapeutic use)