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-β 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-α (p=0.1056), and CCL1 (p=0.1533) were increased, TGF-β (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-α production, increase TGF‐β 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-DRhiCD86hi macrophages may contribute to pathological activity and that CD163hiCD206hi 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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