How NOD2 exerts differential functions is not entirely clear. In the intestine, the suppressive function of NOD2 reportedly involves IFN regulatory factor 4 (IRF4),
22 which is known to interact with MyD88 to negatively regulate TLR signaling.
32 We have found that IRF4 protein is expressed in eye tissue, and its expression is rapidly upregulated by PGN treatment (data not shown here). However, the IRF4 induction was not further influenced by NOD2 genotype, which would not support a mechanism involving IRF4 in the eye. IRF4-independent suppressive functions of NOD2 in intestinal epithelium have recently been reported,
33 suggesting a far more complicated mechanism. Strain, types of host cells, or the specific tissue exposed to pathogens may also influence how NOD2 regulates inflammation. For example, NOD2 KO mice are susceptible to infection with
Listeria only after oral challenge but not intravenous administration,
15 further supporting the tissue-specific role for NOD2 within the intestine for host defense against this pathogen. Our own studies in a murine model of inflammatory arthritis have demonstrated that NOD2 cooperates with TLR2 activation by PGN to promote joint inflammation rather than suppress inflammation as we find in the eye.
34 Within the eye, collectively our studies would suggest that NOD2 exerts dual and paradoxical effects wherein direct activation of NOD2 by MDP promotes inflammation while NOD2 suppresses PGN-triggered inflammation. Such differential roles for NOD2 have also been reported within osteoblasts.
35 A recently described role for PGN in priming systemic innate immune function
36 underscores the importance of NOD1 and NOD2 as homeostatic regulators. This may mean that in the absence of NOD2, protective host responses are lacking, and the eye becomes more susceptible to infection. Interestingly, that we observed differential roles for NOD2 and NOD1 in regulating ocular inflammation would be consistent with what we and others have observed in inflammatory arthritis models.
37 The difference in function may also reflect their ability to distinguish PGN motifs. PGN from
S. aureus used here should lack the meso-DAP motif that stimulates NOD1. Future investigation as to how these 2 NLRs may counterbalance ocular inflammatory responses would be interesting.