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
Open Access
- 21 May 2008
- journal article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 84 (2), 529-536
- https://doi.org/10.1189/jlb.0108015
Abstract
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.Keywords
Funding Information
- National Eye Institute (EY006484, EY013093, EY015137, F32-EY017254)
- Research to Prevent Blindness
- Casey Eye Institute
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