Arthritis Rheumatol. 2026 Sep 1. doi: 10.1002/art.70299. Online ahead of print.
ABSTRACT
OBJECTIVE: To determine whether down-regulation of the transcription factor Fli1 in myeloid cells, previously implicated in profibrotic programming in systemic sclerosis (SSc), promotes cardiac fibrosis and dysfunction in SSc and to define the underlying mechanisms.
METHODS: Immunohistochemistry for Fli1 and galectin-3 (Gal-3) was performed on SSc and control cardiac tissue (n = 6-7). Circulating monocytes were analyzed for Gal-3 protein and messenger RNA (mRNA) levels. Cardiac fibrosis and function were evaluated in young and aged myeloid-specific Fli1 knockout mice (Lyz2Cre/Fli1fl/fl), by collagen staining and echocardiography. Co-culture experiments using human macrophages and primary human cardiac fibroblasts, Fli1 and Gal-3 knockdown, recombinant human Gal-3, and rapamycin were used to dissect mTORC1-dependent profibrotic signaling.
RESULTS: Fli1 expression was reduced (~6-fold, P = 0.0103), whereas Gal-3 was increased (~4-fold, P = 0.0031) in SSc myocardium compared with control. SSc monocytes expressed elevated Gal-3 protein (~2-fold, P = 0.0235) and mRNA levels (~1.7-fold, P = 0.0448). Lyz2Cre /Fli1fl/fl mice had increased myocardial collagen and diastolic dysfunction with elevated mitral E/e' (23.79 ± 8.11 vs 18.76 ± 8.09, P = 0.04) but preserved systolic function; in aged mice, fibrosis was further increased, and systolic function was also impaired (left ventricular ejection fraction 47.41 ± 5.07 vs 66.15 ± 11.49, P = 0.0006). Mechanistically, Fli1 loss derepressed the LGALS3 promoter, increasing Gal-3 in macrophages and activating mTORC1 in cardiac fibroblasts, and Gal-3 or mTORC1 inhibition blunted fibroblast activation.
CONCLUSION: Fli1 deficiency in myeloid cells drives Gal-3-dependent activation of mTORC1 in cardiac fibroblasts, promoting cardiac fibrosis and dysfunction in SSc. These findings identify a myeloid Fli1-Gal-3-mTORC1 axis as a central pathway in SSc-associated cardiac fibrosis and a potential therapeutic target.
PMID:42681974 | DOI:10.1002/art.70299