Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. Although SSc shares pathogenetic features with other autoimmune diseases, the participation of profibrotic Th2 cytokines is unique to SSc. However, the reasons for Th2 cytokine skewing are unknown. Thymic Stromal Lymphopoietin (TSLP) is a pivotal cytokine in induction of Th2 responses in allergic skin and lung inflammation. We have previously observed TSLP overexpression in human and experimental scleroderma (Arthritis Rheum 2011; 63:S904). To understand its function in this context, we have analyzed the contribution of TSLP to Th2 cytokine expression and fibrosis in a mouse model of scleroderma.
Methods: Skin fibrosis was induced in 6 week old female C57BL/6 TSLP receptor (TSLPR) deficient and wild type (WT) mice by subcutaneous injections of bleomycin (1mg/ml) into the shaved back skin daily for 4 weeks. Treated skin was harvested and histological examination and collagen content were determined by Masson’s trichrome staining and total hydroxyproline content. Analysis of cytokines mRNA and protein expression in the skin was performed by quantitative RT-PCR, immunohistochemistry and ELISA. Quantitative data were compared by Mann-Whitney U-test and p-value<0.05 was considered significant.
Results: Bleomycin induced dermal fibrosis and an increase in the collagen content of the skin in both TSLPR deficient and WT mice. The fractional collagen area of the dermis and the total collagen protein content of the skin were significantly reduced in TSLPR deficient mice compared to WT mice. A significant increase in the expression of IL-13 and IL-17 but no IL-4 and IFN-γ mRNA in the skin was observed in bleomycin- injected compared to saline-injected WT mice. Expression of IL-13 and IL-17 mRNA in fibrotic skin was significantly reduced in TSLPR deficient mice compared to WT mice. An increase in the number of IL-13-positive cells by IHC was observed in bleomycin-injected skin compared to saline-injected controls. This response was significantly reduced in TSLPR deficient compared to WT mice. Bleomycin did not increase IL-17 protein expression in either group of mice.
Conclusion: These data provide the first evidence of TSLP contribution to a non-allergic fibrotic process. TSLP profibrotic role is potentially meditated by specific changes in the local cytokine milieu. Thus, modulating TSLP may have anti-fibrotic therapeutic implications.
M. J. Del Rey,
W. J. Leonard,
J. L. Pablos,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tslp-receptor-deficiency-reduces-il-13-expression-and-prevents-fibrosis-in-experimental-scleroderma/