cGAS knockout inhibited endotoxin-induced uveitis in mice

Area of Science:

• Ophthalmology
• Immunology
• Molecular Biology

Background:

• Retinal inflammation, such as uveitis, poses a significant threat to vision.
• The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is implicated in innate immune responses.
• Understanding the role of the cGAS-STING pathway in ocular inflammation is crucial for developing new treatments.

Purpose of the Study:

• To investigate the role of the cGAS-STING pathway in endotoxin-induced uveitis (EIU).
• To evaluate the therapeutic potential of targeting the cGAS-STING pathway for retinal inflammatory diseases.

Main Methods:

• An endotoxin-induced uveitis (EIU) mouse model was established using intravitreal lipopolysaccharide injection.
• Bulk RNA sequencing, PCR, and Western blotting were employed to analyze gene expression and protein activation.
• Cgas knockout mice were utilized to assess the pathway's specific contribution to inflammation.
• Ocular inflammation was evaluated through fundus imaging, fluorescein angiography, histopathology, and leukocytosis assays.

Main Results:

• Analysis revealed activation of the cGAS-STING signaling pathway in the EIU model.
• Cgas knockout mice exhibited significantly reduced intraocular inflammation compared to controls.
• Key indicators of inflammation, including vitreous inflammation, vascular leakage, and leukocyte infiltration, were markedly decreased in Cgas knockout mice.
• Inhibition of macrophage and microglial activation was observed in the absence of cGAS.

Conclusions:

• The cGAS-STING pathway plays a critical role in mediating retinal inflammation in EIU.
• Targeting cGAS demonstrates a potent anti-inflammatory effect in experimental uveitis.
• cGAS represents a promising therapeutic target for managing inflammatory eye diseases like uveitis.