Background/Purpose:

Systemic sclerosis (SSc) is a multisystem fibrotic connective tissue disease characterized by a dysregulated activation of fibroblasts following inflammation, autoimmune attacks, and vascular injuries. Although the pathogenesis of SSc remains currently elusive, chronic activation of wound healing-related gene programs is a hall mark of this disease. Progranulin (PGRN) is a wound healing-associated growth factor with an antagonistic property against tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation, i.e. three major pathological components of SSc. Therefore, we hypothesized that PGRN is involved in the mechanism underlying dermal fibrosis of SSc.

Methods:

PGRN expression levels were determined by immunohistochemistry and quantitative reverse transcription-PCR in the skin of human subjects and murine SSc models. The role of PGRN in dermal fibroblast activation was examined with gene silencing technique. Serum PGRN levels were determined by ELISA in 60 SSc and 16 healthy subjects.

Results:

In immunostaining with human skin samples, the expression levels of PGRN were increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, while comparable in inflammatory cells, endothelial cells, and epidermal keratinocytes between SSc and control subjects. This finding was also confirmed in vitro with cultured SSc dermal fibroblasts, showing a significant increase of PGRN mRNA expression compared with normal dermal fibroblasts. Furthermore, bleomycin-treated mice exhibited the up-regulated expression of PGRN in dermal fibroblasts, suggesting the potential contribution of this molecule to the pathological dermal fibrosis, including SSc. Importantly, transcription factor Fli1, whose deficiency due to epigenetic mechanism contributes to the constitutive activation of SSc dermal fibroblasts, bound to the promoter of the PGRN gene and gene silencing of Fli1 resulted in a robust increase in mRNA levels of the PGRN gene in human dermal fibroblasts. Consistently, the up-regulated expression of PGRN was observed in dermal fibroblasts of Fli1^+/- mice in vivo. Given that PGRN serves as an antagonist of TNF-a, a pro-inflammatory cytokine with a potent anti-fibrotic effect on dermal fibroblasts, we hypothesized that PGRN renders SSc dermal fibroblasts resistant to the anti-fibrotic effect of TNF-a. Supporting our idea, TNF-a suppressed the expression of type I collagen in SSc dermal fibroblasts treated with PGRN siRNA, while not in those treated with non-silencing scrambled RNA. To further assess the role of PGRN in SSc, we measured serum PGRN levels and examined their clinical correlation. Serum PGRN levels were elevated in early diffuse cutaneous SSc patients, especially in those with inflammatory skin symptoms, and positively correlated with C-reactive protein.

Conclusion:

PGRN overproduction due to Fli1 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the anti-fibrotic effect of TNF-a. PGRN may also be involved in the inflammatory process associated with progressive skin sclerosis in early diffuse cutaneous SSc.

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/progranulin-overproduction-due-to-fli1-deficiency-contributes-to-the-resistance-of-dermal-fibroblasts-to-tumor-necrosis-factor-a-in-systemic-sclerosis/