Endothelial Fli1 Deficiency Impairs Vascular Homeostasis

Asano, Yoshihide; Stawski, Lukasz; Hant, Faye N.; Highland, Kristin B.; Silver, Richard M.; Szalai, Gábor; Watson, Dennis K.; Trojanowska, Maria

doi:10.2353/ajpath.2010.090593

Cited by 187 publications

(256 citation statements)

References 55 publications

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“…In particular, it is interesting that IRF5 could serve as a potent repressor for the Tbet gene, because IRF5 acts primarily as a potent inducer of various immune-related and inflammatory genes (17). Also, contrary to our previous findings on serum MMP-13 levels and endothelial VE-cadherin expression in SSc (23,32), Irf5 deficiency induced Mmp13 gene expression in dermal fibroblasts and Cdh5 gene expression in endothelial cells, indicating a role for IRF5 as a transcriptional repressor in various types of cells. In this regard, it may be worth recalling that such a bifunctional action has been shown for IRF3 (20).…”

Section: Discussioncontrasting

confidence: 54%

“…The structural changes of SSc vasculature are largely attributable to vascular instability closely related to the altered phenotype of mural cells. In SSc lesional skin, α-SMA expression is decreased in mural cells, reflecting the weak interaction of endothelial cells with mural cells and the activation of proangiogenic signaling pathways (23). This feature was reproducible in BLM-treated mice, but in Irf5 −/− mice a high α-SMA expression was maintained in the skin vasculature even after BLM injection, indicating that IRF5 is a key regulator of the balance between angiostatic and proangiogenic conditions.…”

Section: Discussionmentioning

confidence: 76%

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Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5−/−) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5−/− mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 76%

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In our study, we found a slight decrease in ECE-1 and no changes in the expression of ET-1 or eNos in endothelial cells from BLM lungs (data not shown). Also observed during scleroderma vascular dysfunction are the loss of vascular endothelial (VE)-cadherin, gaps between endothelial cells, and the loss of vascular integrity (2,36). Contrary to these changes in the vasculature of humans with SSc, we found minimal changes in adhesion molecules known to maintain vascular integrity, including Claudin 5, VE-cadherin, platelet/ endothelial cell adhesion molecule 1 (PECAM1)/CD31, and junctional adhesion molecule 1 (JAM1) (data not shown).…”

Section: Cd45mentioning

confidence: 99%

Endothelial Cells Recruit Macrophages and Contribute to a Fibrotic Milieu in Bleomycin Lung Injury

Leach¹,

Chrobak

Han

et al. 2013

Am J Respir Cell Mol Biol

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“…5,6 Thus, syndecan-1 is inducible in the activated endothelial cells during wound healing, while its expression is marginal in endothelial cells under homeostatic condition. Given that SSc endothelial cells persistently show molecular changes characteristic of pro-angiogenic property, 15 SSc endothelial cells may be a potential source of syndecan-1. Systemic sclerosis vasculopathy is believed to be caused by impaired vascular remodeling due to abnormally activated angiogenesis and defective vasculogenesis.…”

Section: Discussionmentioning

confidence: 99%

Serum level of circulating syndecan‐1: A possible association with proliferative vasculopathy in systemic sclerosis

Asano

Taniguchi

et al. 2015

The Journal of Dermatology

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Syndecan-1 is a member of the transmembrane heparan sulfate proteoglycan family, whose membrane-bound and soluble forms are involved in wound healing, inflammation and vascular biology. Because these physiological events are implicated in the pathogenesis of systemic sclerosis (SSc), we investigated the clinical association of serum syndecan-1 levels in this disease. Serum syndecan-1 levels were significantly higher in SSc patients, both in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc), than in healthy individuals, while comparable between dcSSc and lcSSc groups. In late stage dcSSc patients (disease duration of >6 years), but not non-late stage dcSSc patients (≤6 years), serum syndecan-1 levels were significantly higher than in normal controls. More importantly, SSc patients with elevated serum syndecan-1 levels had higher prevalence of telangiectasia, elevated right ventricular systolic pressure and decreased diffuse capacity of the lung for carbon monoxide than those with normal levels. Therefore, soluble syndecan-1 may be related to the development of proliferative vasculopathy in SSc patients.

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Endothelial Fli1 Deficiency Impairs Vascular Homeostasis

Cited by 187 publications

References 55 publications

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Endothelial Cells Recruit Macrophages and Contribute to a Fibrotic Milieu in Bleomycin Lung Injury

Serum level of circulating syndecan‐1: A possible association with proliferative vasculopathy in systemic sclerosis

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