Background/Purpose: Previous global gene expression studies of SSc patients revealed presence of a prominent type I interferon (IFN) signature. IRF7 is a key transcription factor in the IFN signaling pathway. Polymorphisms in IRF7 gene are associated with SSc susceptibility. In our more recent global gene expression studies examining established disease, IRF7 was predicted to be the most activated upstream transcription factor in SSc skin and blood cells. Therefore, IRF7 might play a key role in the interplay between inflammation and fibrosis in this multifaceted disease. However, the specific role of IRF7 in SSc pathogenesis and fibrosis has not been identified.

Methods: Skin punch biopsies were collected from early diffuse SSc patients (n=57) and age-, gender-, and ethnicity-matched healthy controls (n=33) for global gene expression studies. IRF7 activation was also determined in tight skin 1 (TSK1/+ mouse) model. Next, we investigated the impact of IRF7 KO on skin fibrosis in TSK1 mice. We utilized loss-of-function approaches in TSK1/+ mice, to generate TSK1/+/ IRF7 -/- double transgenic mouse model. Twelve weeks old TSK1+/IRF7 KO mice skin tissue (n=7) was analyzed for collagen, α-SMA and fibronectin mRNA and protein expression.

Results: In agreement with our data in established disease, the global gene expression profiling of early diffuse SSc skin (median disease duration = 1.1 years) revealed that IRF7 was the top activated upstream transcription factor (activation z-score=8.101, p=1.3×10^-25). Several other transcription factors in type I IFN signaling pathway such as STAT1, STAT4, IRF1, and IRF3 were also among top 10 activated transcription factors. Consistent with our previous data in bleomycin induced dermal fibrosis model, TSK1/IRF7 KO transgenic mice showed reduced type I collagen mRNA and protein expression compared to TSK1/+ mice. Col1a2 mRNA levels were lower in TSK1/IRF7 KO mice (1.41 ± 0.21 folds) vs. in TSK1/+ mice (2.64 ± 1.06 folds) compared to control wildtype mice. Hypodermal thickness in TSK1/IRF7 KO mice was also significantly reduced compared to TSK1/+ mice (303.4 ± 72.5 μm Vs. 715.2 ± 161.9 μm; p=0.036). Finally, the myofibroblast marker α-SMA and fibronectin in the skin tissue was also significantly reduced in the TSK1/IRF7 double transgenic mice compared to TSK1/+ mice skin on immunohistochemistry.

Conclusion: Activation of IRF7 might play a pivotal role in the type I IFN driven inflammatory response followed by fibrosis in SSc. IRF7 may therefore represent a promising novel therapeutic target in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-regulatory-factor-irf-7-in-type-i-ifn-signaling-represents-as-a-key-upstream-regulator-in-early-diffuse-ssc-patients-and-plays-critical-role-in-pathogenesis-of-fibrosis/