Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0808478 on January 7, 2009

Published online before print January 7, 2009
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(Journal of Leukocyte Biology. 2009;85:711-718.)
© 2009 by Society for Leukocyte Biology

Activation of nucleotide oligomerization domain 2 exacerbates a murine model of proteoglycan-induced arthritis

H. L. Rosenzweig*,1, M. M. Jann{dagger}, T. T. Glant{ddagger}, T. M. Martin*, S. R. Planck*, W. van Eden§, P. J. S. van Kooten§, R. A. Flavell||, K. S. Kobayashi, J. T. Rosenbaum* and M. P. Davey{dagger}

* Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA;
{dagger} Veterans Affairs Medical Center, Portland, Oregon, USA;
{ddagger} Departments of Biochemistry and Orthopedics, Rush University Medical Center, Chicago, Illinois, USA;
§ Divisions of Immunology and Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands;
|| Department of Immunology, Yale School of Medicine, New Haven, Connecticut, USA; and
Department of Cancer Immunology and AIDS, Harvard Medical School, Boston, Massachusetts, USA

1 Correspondence: Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Stop L467 IM, Portland, OR 97219, USA. E-mail: rosenzwh{at}ohsu.eud

ABSTRACT

In addition to its role in innate immunity, nucleotide oligomerization domain 2 (NOD2) has been shown to play a suppressive role in models of colitis. Notably, mutations in NOD2 cause the inherited granulomatous disease of the joints called Blau syndrome, thereby linking NOD2 with joint disease as well. However, the role of NOD2 in joint inflammation has not been clarified. We demonstrate here that NOD2 is functional within the mouse joint and promotes inflammation, as locally or systemically administered muramyl dipeptide (MDP; the NOD2 agonist) resulted in significant joint inflammation that was abolished in NOD2-deficient mice. We then sought to investigate the role of NOD2 in a mouse model of inflammatory arthritis dependent on adaptive immunity using TCR-transgenic mice whose T cells recognized the dominant epitope of proteoglycan (PG). Mice immunized with PG in the presence of MDP developed a more severe inflammatory arthritis and histopathology within the joints. Antigen-specific activation of splenocytes was enhanced by MDP with respect to IFN-{gamma} production, which would be consistent with the Th1-mediated disease in vivo. Intriguingly, NOD2 deficiency did not alter the PG-induced arthritis, indicating that NOD2 does not play an essential role in this model of joint disease when it is not activated by MDP. In conclusion, we demonstrate that in a model of inflammatory arthritis dependent on T and B cell priming, NOD2 activation potentiates disease. However, the absence of NOD2 does not alter the course of inflammatory arthritis, in contrast to models of intestinal inflammation.

Key Words: NOD2 • mice • inflammatory arthritis • TCR transgenic • knockout