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Published online before print May 21, 2008

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(Journal of Leukocyte Biology. 2008;84:529-536.)
© 2008 by Society for Leukocyte Biology

Activation of NOD2 in vivo induces IL-1β production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling

H. L. Rosenzweig^*,1, T. M. Martin^*,, S. R. Planck^*,,, K. Galster^*, M. M. Jann^¶, M. P. Davey^,,¶, K. Kobayashi^||, R. A. Flavell^** and J. T. Rosenbaum^*,,

^* Departments of Ophthalmology,
Molecular Microbiology and Immunology,
Medicine, and
Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA;
^¶ Veterans Affairs Medical Center, Portland, Oregon, USA;
^|| Department of Cancer Immunology and AIDS, Harvard Medical School, Boston, Massachusetts, USA; and
^** Department of Immunology, Yale School of Medicine, New Haven, Connecticut, USA

¹ Correspondence: Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd., Mail Stop: L467 IM, Portland, OR 97239, USA. E-mail: rosenzwh{at}ohsu.edu

Nucleotide-binding and oligomerization domain 2 (NOD2) belongs to the emerging Nod-like receptor (NLR) family considered important in innate immunity. Mutations in NOD2 cause Blau syndrome, an inherited inflammation of eye, joints, and skin. Mutations in a homologous region of another NLR member, NALP3, cause autoinflammation, wherein IL-1β plays a critical role. Here, we tested the hypothesis that IL-1β is a downstream mediator of NOD2-dependent ocular inflammation. We used a mouse model of NOD2-dependent ocular inflammation induced by muramyl dipeptide (MDP), the minimal bacterial motif sensed by NOD2. We report that MDP-induced ocular inflammation generates IL-1β and IL-18 within the eye in a NOD2- and caspase-1-dependent manner. Surprisingly, two critical measures of ocular inflammation, leukocyte rolling and leukocyte intravascular adherence, appear to be completely independent of IL-1 signaling effects, as caspase-1 and IL-1R1-deficient mice still developed ocular inflammation in response to MDP. In contrast to the eye, a diminished neutrophil response was observed in an in vivo model of MDP-induced peritonitis in caspase-1-deficient mice, suggesting that IL-1β is not essential in NOD2-dependent ocular inflammation, but it is involved, in part, in systemic inflammation triggered by NOD2 activation. This disparity may be influenced by IL-1R antagonist (IL-1Ra), as we observed differential IL-1Ra levels in the eye versus plasma at baseline levels and in response to MDP treatment. This report reveals a new in vivo function of NOD2 within the eye yet importantly, distinguishes NOD2-dependent from NALP3-dependent inflammation, as ocular inflammation in mice occurred independently of IL-1β.

Key Words: transgenic/knockout mice • cytokines