Atorvastatin alleviates the progression of fibrosis in experimental systemic sclerosis: Binding to macrophage CD14 to regulate TLR4/p65 or directly modulating fibroblast Smad3 signaling.

BACKGROUND

Systemic sclerosis (SSc), or scleroderma, is an autoimmune disease with localized/diffuse skin thickening and fibrosis as main features, where disease progression links to inflammatory immunity. Although atorvastatin has anti - inflammatory effects, its role in skin fibrosis is unclear. This study aimed to explore atorvastatin's anti - inflammatory and antifibrotic effects and mechanisms.

METHODS

In vivo, the anti - inflammatory and anti - fibrotic effects of atorvastatin were evaluated using a bleomycin - induced experimental SSc model and a keloid xenograft model. In vitro, an LPS - induced macrophage polarization model and a TGF - β1 - induced fibroblast activation model were employed for research. 16 S rRNA sequencing was conducted to study the skin surface microbiota. To explore the mechanism of action of atorvastatin, methods such as drug affinity reaction target stability technology, molecular docking, and microcalorimetry experiments were adopted.

RESULTS

Atorvastatin alleviated skin fibrosis, reduced thickness, collagen deposition, and macrophage aggregation in mouse models. In vitro, it inhibited macrophage and fibroblast activation. It also improved skin bacteria at the genus level. CD14 was confirmed as a direct target of atorvastatin, and atorvastatin inhibited LPS - TLR4 binding.

CONCLUSIONS

CD14 is a potential therapeutic target for SSc skin fibrosis, and atorvastatin may be a new treatment option.