Inflammatory arthritis in caspase 1 gene–deficient mice: Contribution of proteinase 3 to caspase 1–independent production of bioactive interleukin‐1β

Abstract

Objective: Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro–interleukin‐1β (proIL‐1β), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. Methods: Acute and chronic arthritis were induced in caspase 1−/− mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. Results: Surprisingly, caspase 1−/− mice, in a model of acute (neutrophil‐dominated) arthritis, developed joint swelling to an extent similar to that in wild‐type control mice. Joint fluid concentrations of bioactive IL‐1β were comparable in caspase 1−/− mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1−/− mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1–dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL‐1β concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. Conclusion: Caspase 1 deficiency does not affect neutrophil‐dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL‐1β production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.