alpha(V)beta(8) integrin targeting to prevent posterior capsular opacification

Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor-beta (TCF-beta). Previously, alpha(V) integrins were found to be critical for the onset of TGF-beta-mediated PCO in vivo; however, the functional heterodimer was unknown. Here, beta(8) integrin-conditional knockout (beta(8) ITG-cKO) lens epithelial cells (LCs) attenuated their fibrotic responses, while both beta(5) and beta(6) integrin-null LCs underwent fibrotic changes similar to WT at 5 days post cataract surgery (PCS). RNA-Seq revealed that beta(8) ITG-cKO LCs attenuated their upregulation of integrins and their ligands. as well as known targets of TGF-beta 1-induced signaling. at 24 hours PCS. Treatment of beta(8)ITG-cKO eyes with active IGF-beta 1 at the time of surgery rescued the fibrotic response. Treatment of WT mice with an anti-alpha(V)beta(8) integrin function blocking antibody at the time of surgery ameliorated both canonical TGF-beta 1 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 alpha(V)beta(8) integrin is a major regulator of TGF-beta activation by LCs PCS and that therapeutics targeting alpha(V)beta(8) integrin could be effective for fibrotic PCO prevention and treatment.