Endogenous ligands of TLR4 promote unresolving tissue fibrosis: Implications for systemic sclerosis and its targeted...

Area of Science:

• Immunology
• Pathophysiology
• Fibrosis Research

Background:

• Systemic sclerosis (SSc) is characterized by irreversible fibrosis, a process that fails to resolve unlike normal wound healing.
• Innate immune signaling, particularly via toll-like receptors (TLRs), is increasingly recognized as a critical factor in the persistence of SSc fibrosis.

Purpose of the Study:

• To review the role of the damage-associated molecular patterns (DAMPs)-TLR4 axis in driving sustained fibroblast activation in SSc.
• To discuss the pathogenic mechanisms underlying fibrosis progression in SSc mediated by DAMP-TLR4 signaling.
• To explore potential therapeutic strategies targeting TLR4 signaling for anti-fibrotic approaches in SSc.

Main Methods:

• This review synthesizes current research on innate immune signaling in SSc fibrosis.
• It focuses on the DAMP-TLR4 pathway and its effects on resident mesenchymal cells and fibroblasts.
• The review examines the molecular mechanisms linking DAMPs, TLR4, and profibrotic signaling, including TGF-β.

Main Results:

• Damage-associated molecular patterns (DAMPs), such as fibronectin-EDA and tenascin-C, are generated by recurrent injury in SSc.
• Sensing of DAMPs by TLR4 on resident cells stimulates fibrotic gene expression and myofibroblast differentiation.
• TLR4 activation sensitizes fibroblasts to TGF-β, promoting a persistent fibrotic response instead of self-limited repair.

Conclusions:

• The DAMP-TLR4 axis is a key driver of pathological fibrosis in SSc, promoting sustained fibroblast activation.
• This innate immune signaling pathway underlies the transition from wound healing to non-resolving fibrosis in SSc.
• Targeting TLR4 signaling presents a promising avenue for developing novel anti-fibrotic therapies for SSc.