Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis
Lucy V. Norling, … , Charles N. Serhan, Mauro Perretti
Lucy V. Norling, … , Charles N. Serhan, Mauro Perretti
Published April 21, 2016
Citation Information: JCI Insight. 2016;1(5):e85922. https://doi.org/10.1172/jci.insight.85922.
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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.