αVβ8 integrin targeting to prevent posterior capsular opacification

• Published in: JCI insight 2021-11, Vol.6 (21)
• Main Authors: Shihan, Mahbubul H, Novo, Samuel G, Wang, Yan, Sheppard, Dean, Atakilit, Amha, Arnold, Thomas D, Rossi, Nicole M, Faranda, Adam P, Duncan, Melinda K
• Format: Article
• Language: English
• Subjects: Animals; Capsule Opacification - prevention & control; Cataract - prevention & control; Cell biology; Humans; Integrins - therapeutic use; Mice; Ophthalmology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.145715

Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor-β (TGF-β). Previously, αV integrins were found to be critical for the onset of TGF-β-mediated PCO in vivo; however, the functional heterodimer was unknown. Here, β8 integrin-conditional knockout (β8ITG-cKO) lens epithelial cells (LCs) attenuated their fibrotic responses, while both β5 and β6 integrin-null LCs underwent fibrotic changes similar to WT at 5 days post cataract surgery (PCS). RNA-Seq revealed that β8ITG-cKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGF-β-induced signaling, at 24 hours PCS. Treatment of β8ITG-cKO eyes with active TGF-β1 at the time of surgery rescued the fibrotic response. Treatment of WT mice with an anti-αVβ8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGF-β signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses were established, largely reversed this fibrotic response. These data suggest that αVβ8 integrin is a major regulator of TGF-β activation by LCs PCS and that therapeutics targeting αVβ8 integrin could be effective for fibrotic PCO prevention and treatment.