Background/Purpose: Systemic sclerosis (SSc) is a systemic fibroproliferative disease characterized by concomitant occurrence of microvascular injury and autoantibody production. It has long been suggested that many processes are shared by physiological wound healing and pathological fibrosis. During wound healing process, platelets are the first cells that home to the site of injury, and contribute to the initiation phase through release of a variety of growth factors, chemokines, cytokines, and inflammatory mediators. Circulating platelets in patients with SSc are known to have activated phenotype, but there are few data regarding their functional properties. In this study, we identified potentially fibrogenic factors specifically up-regulated in platelets from SSc patients.  

Methods: We used peripheral blood samples from 49 patients with SSc and 23 age- and sex-matched healthy controls. Proportions of activated platelets and platelet-derived microparticles were examined by expression of an activation marker CD62P using flow cytometry. Genes up-regulated in SSc platelets were screened with the RT² profiler™ PCR array that covered 168 genes, and were subsequently verified by semi-quantitative and TaqMan® quantitative PCR. The protein expression levels of candidate genes were examined by Proteome Profiler or immunoblots combined with densitometry using platelet lysates. We further evaluated roles of platelets or the platelet-derived molecule up-regulated in SSc platelets in production of fibronectin in cultures of human dermal fibroblasts. Finally, effects of CXCL5 on fibronectin production were confirmed in cultures of fibroblasts and SSc platelets in the presence or absence of a chemical antagonist or a neutralizing antibody.

Results: Proportions of activated platelets and microparticles were increased in SSc patients than in healthy controls (P < 0.05 for both comparisons). By stepwise screening strategies based on comparisons of gene/protein expression profiles between SSc and control platelets, CXCL5 was identified as a platelet-derived factor up-regulated in SSc patients. Fibronectin production was greater in fibroblast cultures with SSc platelets, compared with those with control platelets (P < 0.05). Enhanced fibronectin production in cultures with SSc platelets, but not in cultures with control platelets, was partially abolished by a CXCL5 receptor antagonist or a neutralizing antibody to CXCL5. In addition, recombinant CXCL5 promoted in vitro production of fibronectin from fibroblasts.

Conclusion: These results suggest that circulating platelets in SSc patients are phenotypically and functionally altered, and are involved in the fibrotic process through up-regulation of CXCL5.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/up-regulated-expression-of-cxcl5-in-circulating-platelets-from-patients-with-systemic-sclerosis-a-role-in-fibrosis/