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Research Article: TLR7 signaling aggravates lung inflammation associated with increased anti-Scl-70 autoantibody production in murine bleomycin-induced systemic sclerosis

Date Published: 2026-07-01

Abstract:
Systemic sclerosis (SSc) is a severe autoimmune disease characterized by immune dysregulation, fibrosis, and substantial morbidity and mortality. Although type I interferon-related pathways have been implicated in SSc, the contribution of Toll-like receptor 7 (TLR7) and its downstream signaling, including the transcription factor interferon regulatory factor 7 (IRF7) and effector molecules such as CCL2 and CCL12, to disease pathogenesis remains unclear. We used a bleomycin (BLM)-induced mouse model of SSc. Male wild-type (WT), Tlr7 -deficient ( Tlr7 ? / ? ), and Irf7 -deficient ( Irf7 ? / ? ) mice (10–12 weeks old) received daily subcutaneous BLM (2.5 mg/kg/day) for 4 weeks. In a separate experiment, BLM-treated WT mice were treated with the CCR2 antagonist (RS504393). Disease features were evaluated by histopathology, ELISA, flow cytometry, western blotting, RT-qPCR, and Olink proteomics. BLM-treated Tlr7 ? / ? and Irf7 ? / ? mice showed less body weight loss, reduced pulmonary interstitial inflammation, fewer inflammatory monocytes in the spleen, lower pulmonary type I interferon-related gene expression, and lower serum anti-topoisomerase I autoantibody (anti-Scl-70) levels. Pharmacologic CCR2 antagonism attenuated BLM-induced body weight loss, lung injury, and reduced dermal collagen deposition. These findings support a pathogenic role for TLR7-IRF7-IFN-I signaling in anti-Scl-70 autoantibody production and pulmonary inflammation in experimental SSc, and suggest that downstream chemokine pathways may represent therapeutic targets.

Introduction:
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis of the skin and lungs ( 1 ). Despite its low prevalence, SSc has the highest mortality rate among rheumatic diseases. Pulmonary complications are severe, with 50–65% of patients exhibiting interstitial lung abnormalities, and up to 35% of SSc deaths caused by interstitial lung disease (ILD) ( 2 , 3 ). Anti-topoisomerase I (anti-Scl-70) autoantibodies are associated with diffuse…

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