P2X7 receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases

The ATP-gated P2X7 receptor (P2X7R) is a promising therapeutic target in chronic inflammatory diseases with highly specific antagonists currently under clinical trials for rheumatoid arthritis. Anti-inflammatory actions of P2X7R antagonists are considered to result from inhibition of P2X7R-induced release of proinflammatory cytokines from activated macrophages. However, P2X7Rs are also expressed in resting macrophages, suggesting that P2X7R may also signal via cytokine-independent mechanisms involved in joint disease. In this study, we examined P2X7R function in resting human lung macrophages and mouse bone marrow-derived macrophages and found that ATP induced rapid release of the lysosomal cysteine proteases cathepsin B, K, L, and S and that was independent of the presence of the proinflammatory cytokines IL-1β and IL-18. Cathepsins released into the medium were effective to degrade collagen extracellular matrix. ATP-induced cathepsin release was abolished by P2X 7R antagonists, absent from P2X7R-/- mouse macrophages, and not associated with cell death. Our results suggest P2X 7R activation may play a novel and direct role in tissue damage through release of cathepsins independently of its proinflammatory actions via IL-1 cytokines. Copyright © 2010 by The American Association of Immunologists, Inc.