NOD1 expression in the eye and functional contribution to IL-1β -dependent ocular inflammation in mice.

PURPOSE. NOD1 plays an important role in host defense and recognizes the minimal component of bacterial cell walls, meso-diaminopimelic acid (iE-DAP). Polymorphisms in NOD1 are associated with autoinflammatory diseases characterized by uveitis such as Crohn's disease and sarcoidosis. NOD1 is homologous to NOD2, which is responsible for an autosomal dominant form of uveitis. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored. The induction of uveitis by iE-DAP in mice and the potential contribution of interleukin (IL)-1␤ were investigated. METHODS. BALB/c mice or mice deficient in caspase-1 or IL-1R1 and their congenic controls were injected intravitreally with iE-DAP or saline. The time course, dose response, and contribution of IL-1␤ to ocular inflammation were quantified by intravital video microscopy, histology, and immunohistochemistry. NOD1 and IL-1␤ were measured in eye tissue by immunoblotting and ELISA. RESULTS. NOD1 protein is expressed in the eye and promotes ocular inflammation in a dose-and time-dependent fashion. The authors previously defined the role of IL-1␤ in NOD2 uveitis and tested whether NOD1 and NOD2 used similar mechanisms. Treatment with iE-DAP significantly increased IL-1␤, which was caspase-1 dependent. However, in contrast to NOD2, caspase-1 and IL-1R1 were essential mediators of iE-DAP-induced uveitis, suggesting that NOD1 and NOD2 induce ocular inflammation by distinct mechanisms involving IL-1␤. CONCLUSIONS. These findings demonstrate that NOD1 is expressed within the eye and that its activation results in uveitis in an IL-1␤-dependent mechanism. Characterizing the differences between NOD1 and NOD2 responses may provide insight into the pathogenesis of uveitis. (Invest Ophthalmol Vis Sci

Contrasting Ocular Effects of Local versus Systemic Endotoxin

Intraperitoneal and intravitreal injections of endotoxin induce comparable cytokine responses in mouse eyes, but only local injection results in substantial cellular infiltration. This paradox probably results from desensitization of circulating neutrophils when endotoxin is injected systemically

NOD2 Deficiency Results in Increased Susceptibility to Peptidoglycan-Induced Uveitis in Mice

The regulatory roles for NOD2 versus TLR signaling were explored in murine uveitis triggered by peptidoglycan