PXD069871-1

PXD069871 is an original dataset announced via ProteomeXchange.

Title	STING-Dependent Cross-Talk between Cystic Epithelium and Macrophages via IFN-λ2 Promotes Autosomal Dominant Polycystic Kidney Disease
Description	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.
HostingRepository	iProX
AnnounceDate	2025-10-24
AnnouncementXML	Submission_2025-10-24_01:02:50.861.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lu Li
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-24 01:01:36	ID requested
⏵ 1	2025-10-24 01:02:51	announced

Dataset with its publication pending

submitter keyword: ADPKD, cystic epithelium, pro-cystogenic macrophage, cGAS-STING pathway, IFN-λ

Jianhua Mao
contact affiliation	Zhejiang University
contact email	maojh88@zju.edu.cn
lab head
Lu Li
contact affiliation	Zhejiang University
contact email	luli1988@zju.edu.cn
dataset submitter

iProX dataset URI