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
Bhattacharyya, Swati; Varga, John (2018) Endogenous ligands of TLR4 promote unresolving tissue fibrosis: Implications for systemic sclerosis and its targeted therapy. Immunol Lett 195:9-17
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Korman, Benjamin; Marangoni, Roberta Goncalves; Lord, Gabriel et al. (2018) Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis. Arthritis Res Ther 20:145
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Wei, Jun; Zhu, Hongyan; Lord, Gabriel et al. (2017) Nrf2 exerts cell-autonomous antifibrotic effects: compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative. Transl Res 183:71-86.e1
Bhattacharyya, Swati; Wang, Wenxia; Morales-Nebreda, Luisa et al. (2016) Tenascin-C drives persistence of organ fibrosis. Nat Commun 7:11703
Reinke, Lauren; Lam, Anna P; Flozak, Annette S et al. (2016) Adiponectin inhibits Wnt co-receptor, Lrp6, phosphorylation and ?-catenin signaling. Biochem Biophys Res Commun 470:606-612
Bhattacharyya, Swati; Wang, Wenxia; Graham, Lauren Van Duyn et al. (2016) A20 suppresses canonical Smad-dependent fibroblast activation: novel function for an endogenous inflammatory modulator. Arthritis Res Ther 18:216
Taroni, Jaclyn N; Martyanov, Viktor; Huang, Chiang-Ching et al. (2015) Molecular characterization of systemic sclerosis esophageal pathology identifies inflammatory and proliferative signatures. Arthritis Res Ther 17:194
Lakota, Katja; Carns, Mary; Podlusky, Sofia et al. (2015) Serum amyloid A is a marker for pulmonary involvement in systemic sclerosis. PLoS One 10:e0110820

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