The NLRP3 inflammasome pathway contributes to chronic inflammation in experimental autoimmune uveitis.

BACKGROUND: Noninfectious uveitis, a chronic ocular inflammatory disease, is characterized by the activation of immune cells in the eye, with most studies focusing on the role of the adaptive immune system in the disease. However, limited data exist on the potential contribution of the innate immune system, specifically the nucleotide-binding oligomerization domain and leucine-rich repeat receptor-3 (NLRP3) inflammasome pathway. This pathway has previously been identified as a driver of inflammation in several low-grade, progressive inflammatory eye diseases such as diabetic retinopathy. The aim of this study was to determine whether the NLRP3 inflammasome pathway plays a role in the pathogenesis and chronicity of experimental autoimmune uveitis (EAU). METHODS: EAU was induced in C57BL/6J mice via intraperitoneal pertussis toxin and subcutaneous interphotoreceptor retinoid-binding protein injections. After 12 weeks, eyes were enucleated, and whole eye sections were assessed for inflammasome, macrophage, and microglial markers in the retina, ciliary body, and cornea using immunohistochemistry. RESULTS: Our study confirmed higher NLRP3 inflammasome activation (increased expression of NLRP3 and cleaved caspase 1 labeling) in EAU mouse retinas compared to controls. This correlated with increased astrogliosis and microglial activation throughout the eye. Migratory innate and adaptive peripheral immune cells (macrophages and leukocytes) were also found within the retina and ciliary body of EAU mice. Connexin43 proteins, which form hexameric hemichannels that can release adenosine triphosphate (ATP), an upstream inflammasome priming signal, were also found upregulated in the retina and cornea of EAU mice. CONCLUSION: Overall, our findings support the idea that in the EAU model there is active inflammation, even 12 weeks post induction, and that it can be correlated to inflammasome activation. This contributes to the pathogenesis and chronicity of noninfectious uveitis, and our results emphasize that targeting the inflammasome pathway could be efficacious for noninfectious uveitis treatment.