Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. Here, we investigate the impact of a selective PARP-1 inhibitor in experimental arthritis. PARP-1 inhibition with 5-aminoisoquinolinone (AIQ) significantly reduces incidence and severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of AIQ is associated with a striking reduction of the two deleterious components of the disease, i.e. the Th1-driven autoimmune and inflammatory responses. AIQ downregulates the production of various inflammatory cytokines and chemokines, decreases the antigen-specific Th1-cell expansion, and induces the production of the anti-inflammatory cytokine IL-10. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease that leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the bone
Collagen-induced arthritis (CIA) is a murine experimental disease model that shares a number of clinical, histologic and immunologic features with RA, and it is used as a model system to test potential therapeutic agents. 5-aminoisoquinolinone (AIQ) is a new and selective inhibitor of Poly(ADP-ribose) polymerase-1 (PARP-1) previously used for the treatment of various ischemic/reperfusion injuries [17,18]
The initial stages of RA and CIA involve multiple steps, which can be divided into two main phases: initiation and establishment of autoimmunity, and later events associated with the evolving immune and inflammatory responses
Summary
Rheumatoid arthritis (RA) is an autoimmune disease that leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the bone. Th1 cells reactive to components of the joint, infiltrate the synovium, release proinflammatory cytokines and chemokines, and promote macrophage and neutrophil infiltration and activation. Inflammatory mediators, such as cytokines and free radicals, produced by infiltrating inflammatory cells, play a critical role in joint damage [3,4]. Available therapies based on immunosuppressive agents inhibit the inflammatory component of RA and have the potential to slow progressive clinical disability by delaying erosions and deformity (5,6) They neither reduce the relapse rate nor delay disease onset, and because a continued treatment is required to maintain a beneficial effect, they have multiple side effects [5,6]. This illustrates the need for novel therapeutic approaches to prevent the inflammatory and autoimmune components of the disease and to promote immune tolerance restoration
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