AIP1 Regulates Ocular Angiogenesis Via NLRP12‐ASC‐Caspase‐8 Inflammasome‐Mediated Endothelial Pyroptosis

Pathological ocular angiogenesis is a significant cause of irreversible vision loss and blindness worldwide. Currently, most studies have focused on the angiogenesis factors in ocular vascular diseases, and very few endogenous anti-angiogenic compounds have been found. Moreover, although inflammation is closely related to the predominant processes involved in angiogenesis, the mechanisms by which inflammation regulates pathological ocular angiogenesis remain obscure. In this study, a vascular endothelial cells (VECs)-specific anti-angiogenic factor is identified, apoptosis signal-regulating kinase 1(ASK1)-interacting protein-1 (AIP1) as a key pathogenic regulator in a typical ocular angiogenesis model, oxygen-induced retinopathy (OIR), using single-cell RNA sequencing. It is demonstrated that AIP1 inhibited pathological angiogenesis by preventing a particular inflammatory death pathway, namely pyroptosis, in retinal VECs. The assembly of a noncanonical inflammasome is further uncovered, the NLRP12-ASC-caspase-8 inflammasome, which is promoted by decreased AIP1 in OIR. This inflammasome elicited gasdermin D (GSDMD)-dependent endothelial pyroptosis, which in turn promoted the release of vascular endothelial growth factor (VEGF) and interleukin (IL)-1β. Suppression of NLRP12-CASP8-GSDMD axis and AIP1 upregulation reduced VEGF signaling, limiting new vessel formation. These findings reveal a previously uncharacterized inflammatory angiogenic process involving VECs pyroptosis-inducing retinal neovascularization, paving the way for promising therapeutic avenues targeting angiogenesis via AIP1 or pyroptosis.