Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose
Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations that result from fibrosis development, immune activation and vascular injuries. A genome-wide association study showed the involvement of genetic variants in the development of SSc. In particular, a single nucleotide polymorphism within the promoter region of interferon regulatory factor 5 (IRF5) was associated with an increase in SSc. This polymorphism results in a decrease in steady-state IRF5 transcript levels, accompanied with longer survival and milder interstitial lung disease. In this study, we explore the function of IRF5 in the development of SSc utilizing a bleomycin (BLM)-induced SSc mouse model in mice deficient in IRF5 (Irf5-/-mice).
Methods
Wild type (WT) and Irf5-/-mice were induced to develop SSc following BLM treatment. Dermal thickness and fibrosis were measured by histological analyses. The quantity of the collagen-specific amino acid hydroxyproline was also measured. Immunohistochemistry and quantitative reverse transcription-PCR were conducted to evaluate the degree of inflammation and the expression of cytokines, growth factors, chemokines, and cell adhesion molecules.
Results
Dermal and pulmonary fibrosis in BLM-treated Irf5-/- mice was attenuated as compared to WT mice. Consistent with this, inflammatory cell infiltration induced by BLM treatment was suppressed in the mutant mice. Further, IRF5 deficiency modulated the expression of cell adhesion molecules toward the induction of Th1-skewed inflammation by BLM treatment, as represented by the lower expression of intercellular adhesion molecule-1 and glycosylation-dependent cell adhesion molecule-1 in the lesion skin and lung of Irf5-/- mice than in those of wild type mice. Finally, matrix metalloproteinase 13 mRNA and protein expression was higher in the skin and lung of the BLM-treated Irf5-/- mice.
Conclusion
With BLM treatment, Irf5-/- mice exhibited attenuated tissue fibrosis due to the alterations to fibroblasts, immune cells and cell adhesion molecules, indicating a pivotal contribution of IRF5 to pathological tissue fibrosis. As such, our results experimentally lend support to the notion that reduced IRF5 transcripts as a result of a nucleotide polymorphism in the IRF5 promoter region accounts for the attenuation of SSc manifestations.
Disclosure:
R. Saigusa,
None;
Y. Asano,
None;
T. Taniguchi,
None;
Y. Ichimura,
None;
T. Takahashi,
None;
T. Toyama,
None;
A. Yoshizaki,
None;
T. Taniguchi,
None;
S. Sato,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/loss-of-irf5-ameliorates-tissue-fibrosis-in-a-murine-model-of-systemic-sclerosis/