Fibrosis, the hallmark of systemic sclerosis (SSc), represents the transformation of normal wound-healing into a deregulated self-sustaining process. Recent evidence indicates that in SSc injury results in accumulation of tissue breakdown products that can be recognized as danger signals by innate immune sensors. We showed that fibroblasts express and can be activated through toll-like receptors (TLRs) in much the same way that immune cells recognize microbial pathogen-associated patterns. Furthermore,tissue expression of TLR4, and its putative endogenous ligand hyaluronic acid, are both elevated in SSc. We hpothesize that accumulation of endogenous TLR ligands in injured tissue in SSc drives TLR-mediated amplification and persistence of fibroblast activation, resulting in intractable fibrosis. In this proposal we will examine the expression, regulation and function of fibroblast TLRs in SSc.
In Specific Aim 1, we will evaluate cellular TLR4 and endogenous TLR ligand levels in SSc, define a cutaneous "TLR signature", and correlate the tissue TLR signature with clinical parameters in SSc patients.
In Specific Aim 2 we will examine the regulation of TLR expression, and the mechanism of TLR4-dependent fibroblast activation.
In Specific Aim 3 we will examine the role of TLR4 and endogenous TLR4 ligands in scleroderma models using loss-of-function approach, and in Specific Aim 4, we will examine if fibroblast-restricted TLR overexpression can induce the transition of self-limited healing into progressive intractable fibrogenesis. These studies will provide the first insight into the role of fibroblast TLR signaling in the pathogenesis of SSc. The proposed research will accelerate the development of novel anti-fibrotic treatments for SSc.

Public Health Relevance

Systemic sclerosis resembles uncontrolled wound healing, where healing occurs by fibrosis rather than tissue regeneration. The factors responsible for loss of regulatory mechanisms normally controlling wound healing are unknown. We propose that innate immune sensors on lesional fibroblasts are activated within the damaged tissue environment, transforming self-limited repair into intractable fibrosis. These studies will test this hypothesis. The results may elucidate novel strategies for the treatment of SSc.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042309-20
Application #
8461678
Study Section
Special Emphasis Panel (ZRG1-MOSS-G (02))
Program Officer
Tseng, Hung H
Project Start
1993-12-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
20
Fiscal Year
2013
Total Cost
$312,930
Indirect Cost
$107,730
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Varga, John; Hinchcliff, Monique (2014) Connective tissue diseases: systemic sclerosis: beyond limited and diffuse subsets? Nat Rev Rheumatol 10:200-2
Bhattacharyya, Swati; Tamaki, Zenshiro; Wang, Wenxia et al. (2014) FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Sci Transl Med 6:232ra50
Castelino, Flavia V; Varga, John (2014) Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy. Curr Opin Rheumatol 26:607-14
Ghosh, Asish K; Bhattacharyya, Swati; Lafyatis, Robert et al. (2013) p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-*: epigenetic feed-forward amplification of fibrosis. J Invest Dermatol 133:1302-10
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Bhattacharyya, Swati; Kelley, Kathleen; Melichian, Denisa S et al. (2013) Toll-like receptor 4 signaling augments transforming growth factor-* responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol 182:192-205
Bhattacharyya, Swati; Wei, Jun; Varga, John (2012) Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 8:42-54
Zhou, Qiyuan; Pardo, Annie; Konigshoff, Melanie et al. (2011) Role of von Hippel-Lindau protein in fibroblast proliferation and fibrosis. FASEB J 25:3032-44

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