Authors: Sheeline Yu, Buqu Hu, Ying Sun, Xue Yan Peng, Chris J. Lee, Samuel Woo, John McGovern, Jana Zielonka, Tina Saber, Alexander Ghincea, Shifa Gandhi, Anjali Walia, Taylor Pivarnik, Genta Ishikawa, Shuai Shao, Huanxing Sun, Baran Ilayda Gunes, Sophia Kujawski, Stephanie Perez, William Odell, Monique Hinchcliff, John Varga, Carol Feghali-Bostwick, Maor Sauler, Jose L. Gomez, Changwan Ryu, Erica L. Herzog
Published: 2025-06-17
DOI: 10.1183/13993003.01564-2024
Source: Full article
ObjectiveThe lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The cytosolic DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using human biospecimens, cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model.MethodsExpression and localization of cGAS, cytokines, and type 1 interferons were evaluated in SSc-ILD lung tissues, bronchoalveolar lavage (BAL), and isolated lung fibroblasts.CGASactivation was assessed in a publicly available SSc-ILD single cell RNA sequencing dataset. Production of cytokines, type 1 interferons, and αSMA elicited by TGFβ1 or local substrate stiffness were measured in normal human lung fibroblasts (NHLFs)viaqRT-PCR, ELISA, and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human PCLS, and the bleomycin pulmonary fibrosis model.ResultsSSc-ILD lung tissue and BAL are enriched for cGAS, cytokines, and type 1 interferons. The cGAS pathway shows constitutive activation in SSc-ILD fibroblasts and is inducible in NHLFs by TGFβ1 or mechanical stimuli. In these settings, and in PCLS, cGAS expression is paralleled by the production of cytokines, type 1 interferons, and αSMA that are mitigated by a small molecule cGAS inhibitor. These findings are recapitulated in the bleomycin mouse model.ConclusioncGAS signaling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc-ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.