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 4

17R-RvD1 suppresses inflammatory arthritis by limiting leukocyte infiltration to arthritic joints.

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17R-RvD1 suppresses inflammatory arthritis by limiting leukocyte infiltr...
Arthritis was induced with arthritogenic serum (100 μl, i.p. on days 0 and 2). Mice were treated daily with vehicle (0.1% ethanol) or 17R-RvD1 (100 ng), and (A) arthritic score, (B) paw edema, (C) weight loss, and (D) disease incidence were evaluated. Insets in A are representative photographs of hind paw arthritis with and without daily 17R-RvD1 treatment; n = 14–17 mice per group. ***P < 0.001 or *P < 0.05 2-way ANOVA with repeated measures. (E–G) Representative H&E-stained sections of knees from naive and arthritic mice on day 8 after arthritis induction (×4 magnification); n = 5–7 mice per group. Scale bars: 200 μm. F, femur; T, tibia; m, meniscus; IFP, infrapatellar fat pad; PF, pannus formation. (H) Histological score calculated by degree of leukocyte infiltration, cartilage, and bone erosion; n = 5–7 mice per group, *P < 0.05 vs. naive, #P < 0.05 vs. arthritis, 1-way ANOVA with Bonferroni post-hoc test. (I) Plasma KC levels; n = 8–10 mice per group, *P < 0.05 (vs. naive), #P < 0.05 (vs. arthritis) 1-way ANOVA with Bonferroni post-hoc test. (J–L) Arthritic paws were digested to liberate leukocytes; cells were counted by light microscopy and leukocyte subsets defined using specific antibodies by flow cytometry; n = 6 mice per group, *P < 0.05 unpaired Student’s t test. (M) Mice were treated daily following overt signs of arthritis (day 4) for 1 week with vehicle (0.1% ethanol) or 17R-RvD1 (100 ng), and arthritic score was evaluated over 32 days. Arthritis remission indices were calculated; n = 11–12 mice per group.