Antibodies against interleukin-10 receptor reduce IL-6 and TNF-α levels and increase TGF-β levels in patients with severe fever with thrombocytopenia syndrome virus and SARS-CoV-2 infection

초록

Severe fever with thrombocytopenia syndrome virus (SFTSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause severe, often fatal, disease characterized by hyperinflammation and features of a cytokine storm. Hyperproduction of both IL-10 and IL-6 and low TGF-beta production can generate a cytokine storm, with IL-10 playing a particularly important role. To investigate the role of IL-10 in patients with SFTS, we analyzed the phenotypes of macrophages, cytokines, and signaling pathways in patients with mild to fatal SFTS and found that the population of HLA-DR(+)CD86(+) macrophages was increased, the population of CD163(+)CD206(+) macrophages was decreased, the levels of IL-10 (p < 0.0001), IL-6 (p < 0.0001), TNF-alpha (p=0.1056), and CCL1 (p=0.1533) were increased, TGF-beta (p=0.0104) was increased, and Smad3 and P-Smad3 were highly expressed in patients with fatal SFTS. We also investigated the role of IL-10 in THP-1-derived macrophages infected with SFTSV or SARS-CoV-2, treated with lipopolysaccharide (LPS), or treated with serum from patients with fatal SFTS. We found that blocking IL-10 signaling can decrease the population of HLA-DR(+)CD86(+) cells, increase the population of CD163(+)CD206(+) cells, reduce IL-6 and TNF-alpha production, increase TGF-beta production and induce the expression of Smad3 and P-Smad3 in SFTSV- and SARS-CoV-2-infected and LPS-induced THP-1 cells. Additionally, IL-10 receptor blockade can reduce IL-10 and IL-6 production in THP-1 cells treated with serum from patients with fatal SFTS. Therefore, we suggest that HLA-DR(hi)CD86(hi) macrophages may contribute to pathological activity and that CD163(hi)CD206(hi) macrophages may play a critical role in the protection of effector functions against SFTSV and SARS-CoV-2 infection. IL-10 could serve as a prognostic target, and antibodies against the IL-10 receptor could represent a potential immune-based intervention against a cytokine storm in patients with fatal SFTS and severe/critical COVID-19.

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