αVβ8 integrin targeting to prevent posterior capsular opacification (PCO)

Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor β (TGFβ). Previously, αV integrins were found to be critical for the onset of TGFβ-mediated PCO in vivo, however, the functional heterodimer was unknown. Here, β8 integrin conditional knockout (β8ITGcKO) lens cells (LCs) were observed to attenuate their fibrotic responses, while both β5 and β6 integrin null LCs underwent fibrotic changes similar to WT at 5 days PCS. RNAseq revealed that β8ITGcKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGFβ induced signaling at 24 hours PCS. Treatment of β8ITGcKO eyes with active TGFβ1 at the time of surgery rescued the fibrotic response. Treatment of wild type mice with an anti- αVβ8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGFβ signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses are established, largely reversed this fibrotic response. These data suggest that αVβ8 integrin is a major regulator of TGFβ activation by LCs PCS and that therapeutics targeting αVβ8 integrin could be effective for fibrotic PCO prevention and treatment.