Background/Purpose: Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by autoimmunity, vasculopathy, and excessive organ fibrosis. Although the etiology of the disease is still unknown, several lines of evidences suggest the monocytes/macrophages involvement in the pathogenic process of SSc. Interferon regulatory factor 8 (IRF8), a member of IRF family, is a transcriptional regulator that plays essential roles in the differentiation and function of monocytes and macrophages. Genetic association of IRF8 with SSc was reported by genome-wide association study, however, its detailed function is yet to be discovered. In this study, we determined the expression level of IRF8 in circulating monocytes of SSc patients and further analyzed those phenotypic function.

Methods: IRF8 expression levels in peripheral blood mononuclear cells (PBMCs) and circulating monocytes were evaluated by quantitative PCR in 33 patients with SSc (diffuse cutaneous SSc (dcSSc); n=13, limited cutaneous SSc (lcSSc); n=20) and 15 healthy controls in association with clinical characteristics. IRF8 in circulating human monocytes was silenced by RNA interference, then those monocytes were differentiated into macrophages. Cell surface markers, cytokine/chemokine profiles, and expressions of pro-fibrotic factors and extracellular matrix were assessed by flow cytometry and quantitative PCR.

Results: Although no significant difference was observed on IRF8 levels of PBMCs between total SSc patients and healthy controls, dcSSc patients had significantly lower levels of IRF8 compared with healthy controls and lcSSc patients. In addition, that particular downregulation of IRF8 was observed in circulating monocytes from patients with dcSSc. Differentiated macrophages from IRF8-silenced human monocytes tended to exhibit M2 phenotype. Furthermore, mRNA expression levels of tissue growth factor-β, early growth response-1, α-smooth muscle actin, and monocyte chemoattractant protein-1 were significantly upregulated in macrophages from IRF8-silenced monocytes than that in control macrophages. There was also a trend toward increased levels of IL-6 and tumor necrosis factor-α in those macrophages compared to that in controls.

Conclusion: IRF8 was significantly downregulated in circulating monocytes from dcSSc patients and pro-fibrotic phenotype was observed in macrophages differentiated from IRF8-silenced monocytes. IRF8 may play an important role as a key regulator in the pathogenic process of SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/downregulated-expression-of-interferon-regulatory-factor-8-in-circulating-monocytes-exhibits-pro-fibrotic-phenotype-in-patients-with-systemic-sclerosis/