STING-Dependent Cross-Talk between Cystic Epithelium and Macrophages via IFN-λ2 Promotes Autosomal Dominant Polycystic Kidney Disease

ABSTRACT: Background: Autosomal dominant polycystic kidney disease (ADPKD) is primarily driven by mutations in PKD1 or PKD2, but the role of the innate immune microenvironment in disease progression remains poorly understood. While recent studies have implicated the cGAS-STING pathway, the specific mechanisms by which it contributes to cystogenesis, particularly through intercellular communication, are not defined. Methods: We utilized conditional Pkd1 knockout and Sting1 knockout mouse models, human ADPKD kidney samples, and primary cell cultures. Techniques included transcriptomics, proteomics, immunohistochemistry, flow cytometry, and functional assays in macrophages and renal tubular epithelial cells. Results: Pkd1 deficiency induced mitochondrial dysfunction and activated the cGAS-STING pathway in cystic epithelial cells, with phosphorylation of STING correlating with renal fibrosis in human ADPKD. Genetic ablation of Sting1 or its pharmacological inhibition with C176 significantly attenuated cystogenesis, macrophage infiltration, and fibrosis in early-stage disease. Multi-omics analysis revealed that STING inhibition reversed both inflammatory and metabolic abnormalities. We identified IFN-λ2 as a specific downstream effector of STING in cystic epithelium, produced via IRF3 activation. In the immune microenvironment, macrophages from ADPKD patients exhibited heightened expression of the IFN-λ receptor, which was further upregulated by IFN-γ. This primed macrophages to respond to IFN-λ2 by sustaining the production of pro-cystogenic factors (TNF-α, IL-12p40) via prolonged JAK-STAT and MAPK signaling, rather than through classical M1/M2 polarization. Conclusion: Our findings define a pathogenic circuit in ADPKD wherein STING activation in cystic epithelium drives IFN-λ2 production, which in turn sustains a pro-inflammatory, pro-cystogenic phenotype in macrophages. This mechanism highlights the STING-IFN-λ2 axis as a potential therapeutic target, particularly in early-stage disease.

ORGANISM(S): Mus Musculus

SUBMITTER: Jianhua Mao  

PROVIDER: PXD069871 | iProX | Fri Oct 24 00:00:00 BST 2025

REPOSITORIES: iProX