Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Significance: This review provides current overview of the emerging role of innate immunity in driving fibrosis, and preventing its resolution, in scleroderma (systemic sclerosis, SSc). Understanding the mechanisms of dysregulated innate immunity in fibrosis and SSc will provide opportunities for therapeutic interventions using novel agents and repurposed existing drugs. Recent Advances: New insights from genomic and genetic studies implicate components of innate immune signaling such as pattern recognition receptors (PRRs), downstream signaling intermediates, and endogenous inhibitors, in fibrosis in SSc. Recent studies distinguish innate immune signaling in tissue-resident myofibroblasts and bone marrow-derived immune cells and define their roles in the development and persistence of tissue fibrosis. Critical Issues: Activation of toll-like receptors (TLRs) and other PRR mechanisms occurs in resident nonimmune cells within injured tissue microenvironments. These cells respond to damage-associated molecular patterns (DAMPs), such as tenascin-C that are recognized as danger signals, and elicit matrix production, cytokine secretion, and myofibroblast transformation and survival. When these responses persist due to constitutive TLR activation or impaired termination by endogenous inhibitors, they interfere with fibrosis resolution. The genetic basis and molecular mechanisms of these phenomena in the context of fibrosis are under current investigation. Future Directions: Precise delineation of the pathogenic DAMPs, their interaction with TLRs and other PRRs, the downstream signaling pathways and transcriptional events, and the fibroblast-specific regulation and function of endogenous inhibitors of innate immunity, will form the foundation for innovative targeted therapies to block fibrosis by reestablishing balanced innate immune signaling in fibroblasts.

Original publication




Journal article


Adv Wound Care (New Rochelle)

Publication Date





356 - 369


A20, DAMP, SSc, TLR, TNFAIP3/A20, fibroblast, fibronectin-EDA, fibrosis, systemic sclerosis, tenascin-C