Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1beta.
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-1beta (proIL-1beta), 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-1beta 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-1beta 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.


CONCLUSIONS
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-1beta production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.
Joosten
Leo A B
LA
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. l.joosten@aig.umcn.nl
Netea
Mihai G
MG
Fantuzzi
Giamila
G
Koenders
Marije I
MI
Helsen
Monique M A
MM
Sparrer
Helmut
H
Pham
Christine T
CT
van der Meer
Jos W M
JW
Dinarello
Charles A
CA
van den Berg
Wim B
WB
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000378:metabolism*; D007596:Joints / Q000378:metabolism / Q000473:pathology; D019272:Leukocyte Elastase / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053146:Myeloblastin / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D011498:Protein Precursors / Q000378:metabolism*; D012697:Serine Endopeptidases; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000737:chemistry / Q000378:metabolism
D007375:Interleukin-1; D011498:Protein Precursors; C043830:interleukin 1 precursor; D012697:Serine Endopeptidases; D019272:Leukocyte Elastase; D053146:Myeloblastin; D020170:Caspase 1