TLR7 signaling aggravates lung inflammation associated with increased anti-Scl-70 autoantibody production in murine
Jefferson Fernandes Evangelista1,2, Ana Karina Nisperuza Vidal1,2, Donghua Xu1,2
1Division of Comparative Pathology, Tulane National Biomedical Center, Covington, LA, United States.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
