Single-Cell Profiling Reveals Divergent Mechanisms of Fibrosis in Localized Scleroderma and Systemic Sclerosis

Area of Science:

• Dermatology
• Immunology
• Fibrosis Research

Background:

• Localized scleroderma (LoS) and systemic sclerosis (SSc) are fibrotic skin diseases with differing clinical manifestations.
• LoS is characterized by skin-limited fibrosis, while SSc involves systemic organ fibrosis.
• Understanding the distinct molecular mechanisms driving fibrosis in LoS and SSc is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate the underlying mechanisms differentiating LoS and SSc fibrosis.
• To identify key cellular and molecular players involved in LoS and SSc pathogenesis.
• To explore potential therapeutic strategies based on the identified mechanisms.

Main Methods:

• Skin biopsies from healthy controls, LoS patients, and SSc patients were analyzed using immunofluorescence and single-cell RNA sequencing (scRNA-seq).
• In vitro assays and murine models were employed to validate key molecular functions.
• Comparative analysis of immune cell populations and fibroblast characteristics between LoS and SSc was performed.

Main Results:

• Tertiary lymphoid structures (TLS) were significantly more prevalent in LoS lesions (65.7%) compared to SSc lesions (14.3%).
• T follicular helper (Tfh) cells within TLS in LoS were identified, potentially driving local inflammation via the CXCL13/CXCR5 axis.
• Fibroblasts in SSc lesions exhibited high CREB3L1 expression, which promoted fibrotic markers and exacerbated fibrosis in a mouse model, whereas its knockdown alleviated fibrosis.

Conclusions:

• LoS fibrosis is associated with TLS-mediated local immune activation.
• SSc fibrosis is significantly driven by the systemic activation of CREB3L1-expressing fibroblasts.
• Targeting local inflammation may benefit LoS, while targeting CREB3L1 presents a promising antifibrotic strategy for SSc.