Bone morphogenetic protein 4 ameliorates corneal neovascularization by inhibiting NLRP3 inflammasome activation through the promotion of CBP-mediated S100A9 acetylation

Abstract

Corneal neovascularization (CoNV), a common pathological consequence of ocular diseases, leads to vision impairment worldwide. Current therapies have a variety of adverse effects. Our previous studies revealed that bone morphogenetic protein 4 (BMP4) attenuates inflammatory neovascularization. However, the underlying mechanism remains unknown. In this study, we explored the potential role of BMP4 in regulating nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated CoNV. Using a rat CoNV model, we showed that BMP4 significantly reduced suture-induced neovascularization. Specifically, BMP4 inhibited NLRP3 inflammasome activation and changed the global acetylation landscape in the corneas of CoNV model rats. Acetylomic analysis revealed that S100 calcium binding protein A9 (S100A9) acetylation at lysine 59 was significantly facilitated by BMP4 treatment. CREB-binding protein (CBP) was identified as the key acetyltransferase mediating the promotion of S100A9 acetylation by BMP4. Acetylated S100A9 interrupted NLRP3 inflammasome activation and ameliorated CoNV. However, subconjunctival A-485 (CBP inhibitor) injection diminished S100A9 acetylation and abolished anti-inflammatory and antiangiogenic BMP4 effects. Collectively, these findings reveal a novel mechanism underlying the antiangiogenic effect of BMP4 through the promotion of CBP-mediated S100A9 acetylation, which inhibits NLRP3 inflammasome activation. Targeting this mechanism might be a promising approach for the prevention and treatment of corneal inflammation and neovascularization.