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Inflammatory Role of ASC in Antigen-Induced Arthritis Is Independent of Caspase-1, NALP-3, and IPAF¹

Laeticia Kolly^2,*, Mahir Karababa^2,*, Leo A. B. Joosten, Sharmal Narayan^*, Roberto Salvi^*,, Virginie Pétrilli, Jurg Tschopp, Wim B. van den Berg, Alexander Kai-Lik So^* and Nathalie Busso^3,*

^* Service of Rheumatology, Département de l’Appareil Locomoteur, Service of Endocrinology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, and Department of Biochemistry, University of Lausanne, Lausanne, Switzerland; and Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Because IL-1β 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-1β, 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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant K-32K1-116460 from the Fonds National Suisse de la recherche Scientifique and by the Jean and Linette Warnery Foundation.

² L.K. and M.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Nathalie Busso, Service of Rheumatology, Laboratory of Rheumatology, Centre Hospitalier Universitaire Vaudois Lausanne, Nestlé 05-5029, 1011 Lausanne, Switzerland. E-mail address: Nathalie.Busso{at}chuv.ch

⁴ Abbreviations used in this paper: NLR, NOD-like receptor; AIA, Ag-Induced arthritis; mBSA, methylated BSA; SAA, serum amyloid A; LNC, lymph node cell; EGFP, enhanced GFP.