title: P2X(7) receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases.
abstract: The ATP-gated P2X(7) receptor (P2X(7)R) is a promising therapeutic target in chronic inflammatory diseases with highly specific antagonists currently under clinical trials for rheumatoid arthritis. Anti-inflammatory actions of P2X(7)R antagonists are considered to result from inhibition of P2X(7)R-induced release of proinflammatory cytokines from activated macrophages. However, P2X(7)Rs are also expressed in resting macrophages, suggesting that P2X(7)R may also signal via cytokine-independent mechanisms involved in joint disease. In this study, we examined P2X(7)R 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-1beta and IL-18. Cathepsins released into the medium were effective to degrade collagen extracellular matrix. ATP-induced cathepsin release was abolished by P2X(7)R antagonists, absent from P2X(7)R(-/-) mouse macrophages, and not associated with cell death. Our results suggest P2X(7)R activation may play a novel and direct role in tissue damage through release of cathepsins independently of its proinflammatory actions via IL-1 cytokines.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom. gloria.lopez-castejon@manchester.ac.uk
authors.forename: Gloria
authors.initials: G
authors.lastname: Lopez-Castejon
authors.forename: Jill
authors.initials: J
authors.lastname: Theaker
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrin
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clifton
authors.forename: Martin
authors.initials: M
authors.lastname: Braddock
authors.forename: Annmarie
authors.initials: A
authors.lastname: Surprenant
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002401:Cathepsin B / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007592:Joint Diseases / Q000235:genetics / Q000378:metabolism*; D007739:L Cells; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D018124:Receptors, Tumor Necrosis Factor; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: C516674:AZ 11645373; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D018124:Receptors, Tumor Necrosis Factor; D013844:Thiazoles; D000255:Adenosine Triphosphate; D002403:Cathepsins; D002401:Cathepsin B; D000068800:Etanercept; D008727:Methotrexate