Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis
Lucy V. Norling, Sarah E. Headland, Jesmond Dalli, Hildur H. Arnardottir, Oliver Haworth, Hefin R. Jones, Daniel Irimia, Charles N. Serhan, Mauro Perretti
Lucy V. Norling, Sarah E. Headland, Jesmond Dalli, Hildur H. Arnardottir, Oliver Haworth, Hefin R. Jones, Daniel Irimia, Charles N. Serhan, Mauro Perretti
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Research Article Immunology Inflammation

Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis

Abstract

Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which — once applied to human neutrophils — attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor–deficient mice termed ALX/fpr2/3–/–. These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA.

Authors

Lucy V. Norling, Sarah E. Headland, Jesmond Dalli, Hildur H. Arnardottir, Oliver Haworth, Hefin R. Jones, Daniel Irimia, Charles N. Serhan, Mauro Perretti

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Figure 3

Direct actions of RvD1, RvD2, LXA4, and LXB4 on human neutrophil chemotaxis.

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Direct actions of RvD1, RvD2, LXA4, and LXB4 on human neutrophil chemota...
Neutrophils were captured from whole blood of healthy volunteers on P-selectin and ICAM-1–coated microfluidics chambers. Chemotaxis toward an IL-8 gradient (10 nM) was monitored in real time over 30 minutes. During the first 15 minutes, cells were exposed to HBSS + IL-8 (0–10 nM vertical gradient). Then, cells were exposed to a set concentration of resolvin D1 (RvD1), RvD2, lipoxin A4 (LXA4), LXB4 (1 nM), or vehicle (HBSS + 0.1% ethanol) together with the IL-8 gradient over the subsequent 15 minutes. (A) Representative trajectory paths and (B) rose plots of migrating cells are shown. Insets in B show morphology of neutrophils after exposure to IL-8 or proresolving mediators. (C) Quantification of neutrophil chemotaxis index and (D) directness of neutrophil migration as depicted by the graphs; n = 3–4 donors per compound. *P < 0.05, **P < 0.01, and ***P < 0.001 with 2-tailed paired Student’s t tests.