Objective Systemic sclerosis is a progressive connective tissue involving autoimmune processes. It is generally known that members of the TGF-β superfamily are involved in the regulation of connective tissue metabolism in systemic sclerosis (SSc), but also in regulating the immune system. Growth differentiation factor 15 is a distant member of this TGF-β family. We aim to evaluate the role of GDF15 in SSc-pathogenesis.
Methods A longitudinal prospective cohort of SSc patients was screened for GDF15 serum levels by ELISA and associations with disease activity and tissue damage were analysed. Moreover, in vitro stimulation experiments were performed in lung fibroblasts. The role of GDF15 in fibrosis development in vivo was evaluated by performing the bleomycin lung fibrosis model in GDF15 deficient mice.
Results Serum samples from a cohort of 122 patients were screened for GDF15 levels. An increase in GDF15 levels was observed in patients classified as limited SSc, limited cutaneous SSc and diffuse SSc. Moreover, GDF15 serum levels highly correlated with disease activity and clinical symptoms of lung fibrosis. This was also mimicked in the bleomycin mouse model of SSc. Here, bleomycin exposed animals displayed elevated expression levels of GDF15 in lung tissue. Isolated lung fibroblast of GDF15 deficient mice showed reduced induction of IL6 and CCL2 upon bleomycin stimulation compared to wild-type littermates. Both, IL6 and CCL2, are involved in recruitment and activation of the immune system. Surprisingly, no differences in end-stage fibrosis development were observed between wild-type and GDF15 deficient animals after bleomycin injection.
Conclusions An intriguing profile of GDF15 serum levels was found in SSc patients. GDF15 expression is induced during fibrosis development. We hypothesise that the altered GDF15 expression by lung fibroblast may contribute to distorted interaction between the immune system and the stromal connective tissue. From our data it is clear that this protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.
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