Inhibition of Arthritis in the Lewis Rat by Apolipoprotein A-I and Reconstituted High-Density Lipoproteins

Abstract

Objective— This study questions whether high-density lipoproteins (HDLs) and apolipoprotein A-I inhibit joint inflammation in streptococcal cell wall peptidoglycan-polysaccharide (PG-PS)–induced arthritis in female Lewis rats. Approach and Results— Administration of PG-PS to female Lewis rats caused acute joint inflammation after 4 days, followed by remission by day 8. The animals subsequently developed chronic joint inflammation that persisted until euthanasia at day 21. Treatment with apolipoprotein A-I 24 hours before and 24 hours after PG-PS administration reduced the acute and chronic joint inflammation. Treatment with apolipoprotein A-I at days 7, 9, and 11 after PG-PS administration reduced the chronic joint inflammation. Treatment with apolipoprotein A-I or reconstituted HDLs consisting of apolipoprotein A-I complexed with phosphatidylcholine 24 hours before and at days 1, 7, 9, and 11 after PG-PS administration reduced acute and chronic joint inflammation. Treatment with apolipoprotein A-I also reduced the inflammatory white blood cell count, synovial fluid proinflammatory cytokine levels, synovial tissue macrophage accumulation, as well as toll-like receptor 2, and inflammatory cytokine expression. At the molecular level, preincubation of human monocyte–derived macrophages with apolipoprotein A-I or reconstituted HDLs before PG-PS stimulation inhibited the PG-PS–induced increase in toll-like receptor 2 and myeloid differentiation primary response gene (88) mRNA levels, nuclear factor-κB activation, and proinflammatory cytokine production. The effects of apolipoprotein A-I and reconstituted HDLs were abolished by transfecting the human monocyte–derived macrophages with ATP-binding cassette transporter A1 or G1 siRNA. Conclusions— Apolipoprotein A-I and reconstituted HDLs attenuate PG-PS–induced arthritis in the rat. Studies in human monocyte–derived macrophages indicate that this benefit may be because of the inhibition of toll-like receptor 2 expression and decreased nuclear factor-κB activation in macrophages.