Thyroid hormone (TH) regulates cell proliferation, differentiation, and metabolism. Increased TH levels in circulation are associated with a higher incidence of age-related macular degeneration. In mice, TH treatment causes photoreceptor degeneration, which is accompanied by an increase in receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in the retina. Here, we investigated the contribution of RIPK3/necroptosis to TH-induced photoreceptor degeneration using mice deficient in RIPK3 and the necroptotic mixed lineage kinase domain-like protein (MLKL). Wild-type (C57BL/6) and mutant mice at postnatal day 30 received triiodothyronine (T3, 20 µg/mL in drinking water) for four weeks, followed by the evaluation of photoreceptor survival/death and retinal function. Deletion of Ripk3 preserved photoreceptor integrity against T3-induced degeneration, evidenced by improved retinal morphology, increased cone density, improved retinal light responses, and reduced cell death. This protection was observed in both global and photoreceptor-specific Ripk3 knockout mice. In contrast, the deletion of Mlkl did not protect photoreceptors. This work supports the view that RIPK3, but not MLKL, contributes to TH-induced photoreceptor degeneration. The lack of protection from Mlkl deletion suggests that RIPK3’s action is likely mediated via a necrosome-independent mechanism. These findings provide significant insight into how TH signaling induces photoreceptor degeneration and implicate RIPK3 as a potential therapeutic target.
York et al. (Fri,) studied this question.