Modulation of cGAS-STING signaling by PPARα in a mouse model of ischemia-induced retinopathy

Abstract

In ischemic retinopathy, overactivated retinal myeloid cells are a crucial driving force of pathological angiogenesis and inflammation. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling are key regulators of inflammation. This study aims to investigate the association of cGAS-STING signaling with ischemic retinopathy and the regulation of its activation. We found that protein levels of cGAS and STING were markedly up-regulated in retinal myeloid cells isolated from mice with oxygen-induced retinopathy (OIR). Knockout of Sting and pharmacological inhibition of STING both alleviated retinal neovascularization (NV) and reduced retinal vascular leakage in OIR. Further, Sting knockout and STING inhibitor also alleviated leukocyte adhesion to retinal vasculature and infiltration into the retina as well as microglial activation in OIR. These results suggest that cGAS-STING signaling played a pathogenic role in retinal myeloid cell activation and NV in ischemic retinopathy. To identify the regulation of cGAS-STING signaling in OIR, we evaluated the role of transcription factor peroxisome proliferator-activated receptor α (PPARα). The results demonstrated that PPARα was down-regulated in OIR retinas, primarily in myeloid cells. Furthermore, Pparα knockout significantly up-regulated cGAS and STING levels in retinal CD11b + cells, while PPARα agonist inhibited cGAS-STING signaling and cytosolic mitochondrial DNA (mtDNA) release, a causative feature for cGAS activation. Knockout of Sting ameliorated retinal NV, hyperpermeability, and leukostasis in Pparα −/− mice with OIR. These observations suggest that PPARα regulates cGAS-STING signaling, likely through mtDNA release, and thus, is a potential therapeutic target for ischemic retinopathy.

The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage

“…Furthermore, we found that STING was upregulated in microglia/macrophages infiltrating the photoreceptor after LD. Interestingly, during the preparation of the manuscript, Ma et al reported elevated cGAS and STING expression in retinal myeloid cells in oxygen-induced retinopathy (OIR), and knockout or inhibition of STING alleviated microglial activation in OIR [ 42 ]. Therefore, considering our scRNA-seq findings that cGAS-STING components are enriched in retinal microglia/macrophages, suppressing cGAS-STING in retinal microglia/macrophages cells may be beneficial in treating retinal degenerative diseases and retinopathy.…”

Therapeutic Potential of Biochanin A in Herpes Simplex Keratitis

“…Although these immune responses are intended to be protective, the cytokines generated by immune cells reduce visual acuity by causing fibrosis and inflammation [ 37 ]. It has been documented that HSV-1 can induce cGAS-STING signaling, which is an important cytosolic DNA sensor mechanism in innate immunity and an immune inflammatory route, and the activated STING initiates a sequence of downstream pathway activation and events that transcriptionally up-regulate inflammatory cytokines and other factors, such as IL-6, TNF-α and RANTES [ 38 , 39 , 40 , 41 ]. The hyperproduction of pro-inflammatory cytokines can drive pathological inflammation and exacerbate HSK [ 42 ].…”

Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization

“…After homogenizing the image scale, the boundaries of the CNVs were delineated using the free selection tool and displayed in square micrometers (μm 2 ) [ 27 , 28 ]. Delineation of neovascular and avascular areas in OIR mice were referred to previous studies [ 29 , 30 ].…”