Although it is generally agreed that transforming growth factor-beta (TGF?) plays a central role in sustaining fibrosis in systemic sclerosis (SSc), the triggers of TGF?, TGF? activation and TGF? intracellular signaling are still unknown. The goal of this grant is to understand how TGF? signal activation is up-regulated in SSc focusing on the link between innate immunity, inflammation and fibrosis. New emerging evidence points to the importance of innate immunity and interferons (IFNs) in many autoimmune diseases including SSc, and we found that in addition to upregulated TGF? gene expression SSc skin and peripheral blood mononuclear cells (PBMC) also show upregulated IFN gene expression. Interestingly more recently we found that polyIC, a toll like receptor 3 (TLR3) ligand, activates human fibroblasts (fb), inducing not only genes known to be regulated by IFNs but also genes that are induced by TGF?, suggesting that TGF? activation and then fibrosis is regulated by the innate immune response. Thus this application proposes to investigate how innate immune activation regulates inflammation and scarring through cross talk between IFN?/?and TGF?. One of the most exciting of our preliminary results is that polyIC and IFN? both induce Smad1 phosphorylation, indicating crossactivation of TGF? signaling by IFN?/?. In addition we unexpectedly discovered that IFN? a receptor 2 (IFNAR2) in mice deficient of the IFN? receptor 1 (IFNAR1 -/-) activates a """"""""non classical"""""""" IFN?/? pathway, and that this pathway may be involved in entirely new biological functions such as controlling the induction of TGF? signaling components. In the first aim, proposed experiments will examine the mechanism controlling the physiologic balance between the induction and suppression of the pro-inflammatory program through cross talk between IFN and TGF? in fb from wild type (WT) mice, studying Smad1/2/3 expression and phosphorylation, IRF7 and Smad7 gene expression. Then we will investigate the consequences of aberrant IFN signaling that promote novel cross talk between IFN and TGF?, and causing the modified equilibrium in TLR activation promoting the profibrotic phenotype in fb from IFNAR1-/- mice.
Aim 2 will explore whether impairment of IFN?/? signaling might underlie the pro-fibrotic phenotype that characterizes SSc fb, as we observed in IFNAR1 -/- fb. Experiments in this aim will test the effect of IFN? and polyIC on TGF? signaling components and the functioning of INF?/? signaling in SSc compared to normal fb. Finally we will examine the in vivo expression of selected IFN?/? and TGF? mediators IRF7 and Smad7, in SSc and control skin. Together, these results should significantly extend our understanding of the role of innate immune activation, IFNs and TGF? in dermal fibrosis, enlightening a new standpoint of SSc pathogenesis that IFN?/? impairment might be the primary cause of uncontrolled TGF? activation. In addition the new finding of IFNAR2 function in controlling activation of TGF? signaling, add a novel biological response to the complexity of IFN-mediated signaling potentially influencing the clinical use of therapeutics targeting IFNs not only in SSc but also in other diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR062721-03
Application #
8639482
Study Section
Special Emphasis Panel (ZAR1-EHB (M1))
Program Officer
Tseng, Hung H
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$80,213
Indirect Cost
$31,213
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Farina, Antonella; Farina, G Alessandra (2016) Fresh Insights into Disease Etiology and the Role of Microbial Pathogens. Curr Rheumatol Rep 18:1
Rice, Lisa M; Padilla, Cristina M; McLaughlin, Sarah R et al. (2015) Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest 125:2795-807
Lenna, Stefania; Assassi, Shervin; Farina, G Alessandra et al. (2015) The HLA-B*35 allele modulates ER stress, inflammation and proliferation in PBMCs from Limited Cutaneous Systemic Sclerosis patients. Arthritis Res Ther 17:363
Mathes, Allison L; Christmann, Romy B; Stifano, Giuseppina et al. (2014) Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann Rheum Dis 73:1864-72
Farina, Antonella; Cirone, Mara; York, Michael et al. (2014) Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol 134:954-64
van Bon, Lenny; Affandi, Alsya J; Broen, Jasper et al. (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433-43
Ghosh, Asish K; Bhattacharyya, Swati; Lafyatis, Robert et al. (2013) p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis. J Invest Dermatol 133:1302-10
Lenna, Stefania; Farina, Alessandra G; Martyanov, Viktor et al. (2013) Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension. Arthritis Rheum 65:1357-66
Lenna, Stefania; Chrobak, Izabela; Farina, G Alessandra et al. (2013) HLA-B35 and dsRNA induce endothelin-1 via activation of ATF4 in human microvascular endothelial cells. PLoS One 8:e56123
Lafyatis, Robert; Farina, Alessandra (2012) New insights into the mechanisms of innate immune receptor signalling in fibrosis. Open Rheumatol J 6:72-9

Showing the most recent 10 out of 17 publications