Background/Purpose: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates key cellular processes such as proliferation, apoptosis, invasion, angiogenesis, metastasis and immune responses. STAT3 can be phosphorylated and activated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). We hypothesized that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis.

Methods:  Activation of STAT3, JAK1, JAK2, SRC, c-ABL and JNK was analyzed in SSc patients and in experimental models of SSc by real-time PCR, Western Blot and immunohistochemistry. Selective inhibitors in conjunction with knockdown and knockout strategies were used to target STAT3 signaling and its upstream kinases in vitro and in vivo. The anti-fibrotic potential of genetic and pharmaceutical inactivation of STAT3 was evaluated in two mouse models of SSc: bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active TGFβ receptor type I (TBRact).

Results:  Accumulation of phosphorylated and thus active STAT3 (P-STAT3) was detected in fibroblasts in the skin of SSc patients as compared to healthy volunteers. Enhanced STAT3 signaling was also found in murine models of SSc. The upregulation of P-STAT3 was found to be mediated by TGFβ signaling. Expression profiling and functional studies in vitro and in vivodemonstrated that the activation of STAT3 is mediated by the combined action of JAK, SRC, c-ABL and JNK kinases. STAT3-deficient fibroblasts were less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3 also ameliorated experimental fibrosis. In the model of bleomycin-induced fibrosis, dermal thickening was decreased by 77%, collagen content by 52% and myofibroblast counts by 58% compared to compared to littermates with normal expression of STAT3. STAT3 knockout mice were also protected from TBRact-induced fibrosis. Pharmacological inhibition of STAT3 using the small molecule inhibitor S3I-201 exerted potent anti-fibrotic effects and inhibited TGFβ-induced fibroblast activation, bleomycin- and TBRact-induced experimental fibrosis in pharmacologically relevant and well tolerated doses.

Conclusion:  We demonstrate that STAT3 integrates several profibrotic signals in SSc and might thus be a novel core mediator of fibrosis. Inhibition of STAT3 prevented fibroblast activation and demonstrated potent anti-fibrotic effect in different preclinical models of SSc. Considering the potent anti-fibrotic effects observed in this study and the fact that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be an interesting candidate for molecular targeted therapies of SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stat3-as-an-important-integrator-of-profibrotic-pathways-in-systemic-sclerosis/