Abstract
Purpose :
Pathological retinal angiogenesis is a typical manifestation of various vision-threatening ocular diseases. However, the role of inflammation and myeloid cell activity in retinal angiogenesis remains to be investigated. Bruton's tyrosine kinase (BTK) plays a momentous role in hematologic angiogenesis-dependent tumors, and myeloid function. Therefore, we innovatively examine the suppressive effect of BTK inhibitors on retinal angiogenesis of oxygen-induced retinopathy (OIR) mice, aiming to validate the anti-inflammatory and anti-angiogenic effects of BTK inhibition and provide a novel target for retinal neovascularization.
Methods :
The inhibition of retinal angiogenesis and vascular leakage after intravitreal administration of Acalabrutinib (a highly selective BTK inhibitor) was determined with immunofluorescence staining of retinal vasculature and erythrocyte extravasation in OIR retinas at postnatal day 17. We removed retinal microglia and lymphocytes using PLX5622 administration and Rag1 knockout mice, respectively, to examine the therapeutic pathway. We detected the cytokines, activation markers, morphology, and inflammatory activity of retinal microglia/macrophages by qRT-PCR and immunofluorescence.
Results :
BTK inhibition dramatically suppresses pathological angiogenesis and vascular leakage and reduces retinal inflammation, showing the therapeutic effects through microglia/macrophages, but not lymphocytes. BTK inhibition reduces the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and modulates the number of macrophages, polarizes retinal microglia from a CD86-positive inflammatory activated state to an immune regulatory state, and is synergistic with anti-vascular endothelial growth factor (VEGF) therapy, without retinal toxicity.
Conclusions :
BTK inhibition significantly suppresses pathological retinal angiogenesis and vascular leakage by modulating the inflammatory activity of retinal microglia/macrophages. The present results suggest BTK inhibition as a novel and crucial therapeutic approach to alleviate pathological angiogenesis, and contribute to the development of clinical translation and clinical trials for ophthalmic inflammatory and neovascular diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.