Inflammatory role of ASC in antigen-induced arthritis is independent of caspase-1, NALP-3, and IPAF.
Because IL-1beta plays an important role in inflammation in human and murine arthritis, we investigated the contribution of the inflammasome components ASC, NALP-3, IPAF, and caspase-1 to inflammatory arthritis. We first studied the phenotype of ASC-deficient and wild-type mice during Ag-induced arthritis (AIA). ASC(-/-) mice showed reduced severity of AIA, decreased levels of synovial IL-1beta, and diminished serum amyloid A levels. In contrast, mice deficient in NALP-3, IPAF, or caspase-1 did not show any alteration of joint inflammation, thus indicating that ASC associated effects on AIA are independent of the classical NALP-3 or IPAF inflammasomes. Because ASC is a ubiquitous cytoplasmic protein that has been implicated in multiple cellular processes, we explored other pathways through which ASC may modulate inflammation. Ag-specific proliferation of lymph node and spleen cells from ASC-deficient mice was significantly decreased in vitro, as was the production of IFN-gamma, whereas IL-10 production was enhanced. TCR ligation by anti-CD3 Abs in the presence or absence of anti-CD28 Abs induced a reduction in T cell proliferation in ASC(-/-) T cells compared with wild-type ones. In vivo lymph node cell proliferation was also significantly decreased in ASC(-/-) mice, but no effects on apoptosis were observed either in vitro or in vivo in these mice. In conclusion, these results strongly suggest that ASC modulates joint inflammation in AIA through its effects on cell-mediated immune responses but not via its implication in inflammasome formation.
Kolly
Laeticia
L
Service of Rheumatology, Département de l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois and University of Lausanne, University of Lausanne, Lausanne, Switzerland.
Karababa
Mahir
M
Joosten
Leo A B
LA
Narayan
Sharmal
S
Salvi
Roberto
R
Pétrilli
Virginie
V
Tschopp
Jurg
J
van den Berg
Wim B
WB
So
Alexander Kai-Lik
AK
Busso
Nathalie
N
D000818:Animals; D000941:Antigens / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency*; D001169:Arthritis, Experimental / Q000209:etiology* / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000172:deficiency*; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000172:deficiency*; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000502:physiology*; D007249:Inflammation / Q000209:etiology*; D007592:Joint Diseases / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013154:Spleen / Q000473:pathology
D000941:Antigens; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C512299:Ipaf protein, mouse; D046912:Multiprotein Complexes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D020170:Caspase 1