CCL17 and IL-10 as Effectors That Enable Alternatively Activated Macrophages to Inhibit the Generation of Classically Activated Macrophages

Classically activated macrophages (CAMφ) have been described as a major effector cell on the host's innate immunities. However, CAMφ are not generated in immunocompromised hosts whose alternatively activated macrophages (AAMφ) predominate. In this study, the mechanism by which AAMφ suppress the ability of resident macrophages (RMφ) to generate CAMφ was investigated. AAMφ were isolated from peritoneal exudates of mice 2 days after third-degree thermal injuries affecting 15% total body surface area. CAMφ were generated from RMφ (peritoneal Mφ from normal mice) through stimulation with CpG DNA, a typical CAMφ inducer. RMφ did not polarize to CAMφ when they were cultured with AAMφ in a dual-chamber Transwell even when supplemented with CpG DNA. In addition, RMφ stimulated with CpG DNA did not convert to CAMφ when they were cultured with the culture fluids of AAMφ (AAMφ Culture-Sup). AAMφ Culture-Sup contained IL-6, IL-10, CCL17, PGE₂, and TGF-β. Among these, CCL17 and IL-10 inhibited CAMφ generation. The ability of AAMφ Culture-Sup to inhibit CAMφ generation was eliminated when the Culture-Sup was treated with a mixture of mAbs directed against CCL17 and IL-10. These results indicate that CCL17 and IL-10 released from AAMφ inhibit CAMφ generation from RMφ stimulated with CpG DNA.