IFN-γ-Associated Signaling Networks in Interstitial Lung Disease Associated With Sjögren's Disease.

Authors

Qianqian Chen, Yuhan Li, Yiming Chen, Yuhua Su, Xiaodong Wang, Chunxiao Guan

Published in

Immunity, inflammation and disease. Volume 14. Issue 10. Pages e70547.

Abstract

Sjögren's disease (SD) is a chronic systemic autoimmune disorder that can affect multiple organ systems. Interstitial lung disease (ILD) is a clinically significant pulmonary manifestation of SD and is associated with impaired quality of life and increased mortality. Interferon-γ (IFN-γ), a major effector cytokine of Th1 immunity, has been implicated in immune dysregulation and chronic inflammation; however, its contribution to SD-associated ILD (SD-ILD) and its relationship with fibrotic remodeling remain incompletely understood.
This pathway-oriented narrative review synthesized evidence identified through a structured and iterative search of PubMed, Embase, and Web of Science, updated through August 2026. Priority was given to direct evidence from SD-ILD. When disease-specific evidence was limited, mechanistic findings from SD without characterized ILD, related connective tissue disease-associated ILDs, fibrotic lung diseases, and experimental models were considered and interpreted as indirect or extrapolated evidence.
Available evidence supports a conceptual network in which IFN-γ may function as a potential signaling node interacting with JAK/STAT, PI3K/AKT, NF-κB, MAPK, WNT/β-catenin, and IDO-kynurenine-AhR pathways. These pathways may contribute at different levels to immune-cell activation, inflammatory amplification, immunometabolic regulation, epithelial injury, fibroblast activation, and fibrotic remodeling. Evidence is strongest for the biological relevance of IFN-γ-JAK/STAT signaling, whereas support for PI3K/AKT, NF-κB, and MAPK is more indirect, and the relevance of WNT/β-catenin and particularly IDO-Kyn-AhR to SD-ILD remains less well established.
The proposed IFN-γ-associated network should be regarded as a conceptual mechanistic framework rather than a fully validated signaling hierarchy in SD-ILD. Distinguishing direct disease-specific evidence from mechanistic extrapolation highlights important knowledge gaps and provides a rationale for future investigation of pathway-informed biomarkers and stage-specific therapeutic strategies. Prospective SD-ILD studies integrating longitudinal clinical data with spatial and single-cell approaches are needed to validate these relationships and clarify their translational relevance.

PMID:
42836588
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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