A specific IKKβ inhibitor suppresses experimental autoimmune uveoretinitis in mice

Abstract

Purpose : Experimental autoimmune uveoretinitis (EAU) is a widely used animal model to investigate human endogenous uveitis, in which the transcriptional factor nuclear factor-κB (NF-κB) is involved in its pathogenesis. Activation of IκB kinase (IKK) degrades IκB, resulting in NF-κB translocation to nuclei and leading to expression of pro-inflammatory cytokines and the subsequent inflammatory process. In the current study, the therapeutic effects of a specific IKKβ inhibitor, IMD-0354, was examined in EAU.

Methods : EAU was induced in B10.BR mice by injection of interphotoreceptor retinoid binding protein derived K2 peptide emulsified with complete Freund’s adjuvant. Bordetella pertussis toxin was also injected as an additional adjuvant. IMD-0354 (30 mg/kg) was injected intraperitoneally every 3 days. Clinical and histopathological severities were graded. Translocation of NF-κB p65 into the nuclei was assessed by immunohistochemistry. T cells were collected from draining lymph nodes of the immunized mice to examine antigen-specific T-cell proliferation and inflammatory cytokine production in vitro.

Results : IMD-0354-treated mice exhibited milder EAU clinical severity (Ave; 1.8+0.45) and histopathological severity (Ave; 0.63+0.44), compared to the controls (Ave; clinical severity:3.2+0.63; histological severity; 2.6+0.84, p<0.01). Inhibition of NF-κB p65 translocation into the nuclei of retina was observed (p<0.01). No significant difference was observed in the antigen-specific T cell proliferation between treated and control groups. IMD-0354 treatment significantly suppressed inflammatory cytokines including tumor necrosis factor alpha alpha, interferon gamma, interleukin 1 alpha, interleukin 6, interleukin-17A, compared to that of controls.

Conclusions : Administration of the specific IKKβ inhibitor, IMD-0354, significantly inhibited NF-κB translocation into the retina, which subsequently suppressed the inflammatory response in EAU model. These results suggest that IMD-0354 is a promising therapeutic agent for endogenous uveitis.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.