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K. T. Galster, H. L. Rosenzweig, T. Kawaguchi, S. R. Planck, J. T. Rosenbaum; Treatment With the NOD1 Agonist Results in Ocular Inflammation in Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5148. doi: https://doi.org/.
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NOD1 functions as an intracellular pattern recognition receptor in defense against invasive bacteria and is activated in response to a component of bacterial cell walls, γ-D-Glu-mDap (iE-DAP). Polymorphisms in the NOD1 gene are associated with Crohn’s disease, sarcoidosis and atopic dermatitis. NOD1 is expressed in eyes and may play a role in the pathogenesis of inflammatory diseases with coincident uveitis. Here, we sought to test whether activation of NOD1 results in ocular inflammation in mice.
iE-DAP, iE-Lys (an inactive derivative of iE-DAP) or saline was injected into the vitreous of female, BALB/c mice. The inflammatory response within the iris was assessed by intravital video microscopy, and the numbers of rolling, adherent and extravasated cells within the iris were determined at 5 and 24 hours postinjection. Production of IL-1β and IFNγ in the eye was assessed by ELISA.
To determine the dose-dependent effects of iE-DAP, mice were injected with 25 to100 µg of iE-DAP. At 5 h post treatment, 100 µg of iE-DAP elicited the most inflammation, with a significant increase in the number of rolling (850+193 vs 144+63 cells/mm2/min in saline controls, p<0.05), adherent (551+185 vs 45+22 cells/mm2 in saline controls, p<0.05) and extravascular leukocytes (532+149 vs 66+9 cells/mm2 in saline controls, p<0.05). As expected, injection of 100 µg of ie-Lys did not induce inflammation. Examination at 24 h post-treatment revealed that mice injected with 100 µg ie-DAP had a sustained increase in the numbers of adherent (495+80 vs 85+24 cells/mm2 in saline controls) and extravascular cells (745+ 67 vs 109+21 cells/mm2 in saline controls). Because activation of NOD2 increases IL-1β and IFNγ production in the eye, we determined if activation of NOD1 also increases levels of these cytokines. Mice treated with 100 µg ie-DAP had increased IL-1β levels at 5 h following treatment (253+38 vs 99.4+18.9 pg/ml saline controls, p<0.05) and IFNγ levels were increased at 24 h treatment (36.6+5 vs 22.5+2.7 pg/ml saline controls, p<0.05).
Our findings suggest that activation of NOD1 by intravitreal injection of ie-DAP triggers ocular inflammation. The kinetics of this response are slightly different from those that we previously found for NOD2 activation (Rosenzweig et al., IOVS, in press). Characterizing the differences in NOD1 versus NOD2 responses may provide insight into the pathogenesis of ocular inflammation.
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