Abstract
Purpose: :
Sterile inflammation, an inflammatory response to non-infectious pathogens, underlies the pathogenesis of a number of retinal diseases including autoimmune uveoretinitis, retinal ischemic injuries, diabetic retinopathy, and age-related macular degeneration. Although extensive studies have been carried out in the context of retinal autoimmune diseases, little is known on how retinal immune system responds to de novo non-infectious pathogens. In this study, we investigated retinal immune response to sterile cell death.
Methods: :
Adult C57BL/6 mice were injected intravitreally with 0.75 uM paraquat. Retinal changes were monitored clinically with topic endoscopic fundus examination (TEFI). At different days post-injection (p.i.), mice were sacrificed and eyes collected for histological investigations by light-, confocal- and electron microscopy, as well as for molecular investigation by real-time RT-PCR.
Results: :
Twenty-four hours after paraquat injection, many propidium iodide positive necrotic cells were detected in the retina. Retinal oedema was observed by TEFI within 1-2 days p.i., and after one week, retinal degeneration became evident. Necrotic cell death was further confirmed by transmission electron microscopy. Microglial activation occurred as early as 12 h p.i., followed by neutrophil infiltration at 2 days p.i. The number of infiltrating neutrophils increased as the disease progressed; however, the majority of the cells were confined in the inner retina. In contrast, activated macrophages/microglia were observed throughout different layers of the retina and many of the cells exhibited multiple intracellular inclusions. Following paraquat injection, the expression of IL-1β, Nlrp3 and caspase-1 increased significantly in the retina. The treatment, however, did not affect the expression of complement C3, C4, and factor B, or the deposition of C3d in the retina.
Conclusions: :
Necrotic cell death in the retina induces an acute inflammatory response characterised by neutrophil and macrophage infiltration. Nlrp3 inflammasome may play an important role in necrotic cell death-mediated retinal inflammation.
Keywords: immunomodulation/immunoregulation • retina • apoptosis/cell death