Involvement of epidermal growth factor receptor pathway in experimental autoimmune uveoretinitis

Abstract

Purpose : Recently, it has been reported that the epidermal growth factor receptor (EGFR) pathway is involved in various inflammatory diseases. In this study, we investigated the involvement of EGFR pathway in experimental autoimmune uveoretinitis (EAU).

Methods : To induce EAU, 7-week-old C57BL/6 mice were immunized by subcutaneous injection of an emulsion of interphotoreceptor retinoid binding protein derived peptide and complete Freund's adjuvant (CFA), and pertussis toxin (PTX) was injected intraperitoneally as an additional adjuvant. On day 14 after immunization, the expression of EGFR and EGF family mRNA in the retinochoroidal tissue were measured and compared with that in control mice in which only CFA and PTX were administered. For betacellulin (BTC), a member of EGF family, mRNA expression level was measured over time. Next, on day 16 after immunization, the level of BTC protein in the retinochoroidal tissue and in the serum was measured by ELISA and compared with that in control mice. To examine the effect of EGFR inhibitor, EAU-induced mice were treated with intraperitoneal gefitinib, an EGFR pathway inhibitor, and clinical and histological severity score of EAU were evaluated compared to those in the control mice in which only vehicle (dimethyl sulfoxide; DMSO) was administered.

Results : Among the EGFR and EGF families, only BTC mRNA expression was elevated in the retinochoroidal tissue of EAU-induced mice, and the expression level was significantly elevated on day 14 and day17 after immunization. Relative mRNA expression compared to control was 4.97 ±1.68 on day 14 (p<0.05) and 1.65 ±0.20 on day 17 (p<0.01). The BTC protein level in the retinochroidal tissue of EAU-induced mice (355 ±100 pg/mg) was significantly increased than in that of control mice (211 ±53 pg/mg) (p<0.01). BTC protein level in the serum was below the detection limit even in EAU-induced mice. In the inhibition experiment, the clinical severity score of EAU was reduced in gefitinib-treated mice (0.41 ±0.51) than untreated control mice (3.2 ±1.1) on day 16 after immunization (p<0.01). The histological severity score of EAU was reduced in gefitinib-treated mice (0.42 ±0.63) than untreated control mice (1.6 ±0.51) on day 19 after immunization (p<0.01).

Conclusions : Our results suggest that the EGFR pathway is involved in the pathogenesis of EAU, and the ligand is BTC in the pathway.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.