Characterization of Interleukin-27-induced HIV-Resistant Human Monocyte-derived Macrophages: Implication of the Induction of a Novel Subset of Macrophages in vitro

M2 macrophages can be polarized into M2a, M2b, M2c, and M2d by various stimuli, and Interleukin (IL)-27-treated M2 macrophages (27-Mac) resists HIV infection. Since IL-27 is a member of IL-6 family of cytokines, and IL-6 polarizes M2 macrophages into M2d, 27-Mac was considered an M2d-like cells. In the current study, we compared 27-Mac and M2d and characterized 27-Mac. Monocytes derived from health donors were differentiated to M2 using M-CSF, and then the resulting M2 were polarized into subtypes using IL-6, IL-27, or BAY60-658 (an adenosine analog which polarizes M2 into M2d). Although IL-6 and IL-27 share gp130 to induce STAT3 signaling pathway, only 27-Mac resisted HIV infection and enhanced the generation of reactive oxygen species (ROS). In contrast, BAY60-6583-polarized M2 macrophages (BAY-M2d) resisted HIV infection without affecting ROS production. The cytokine-producing profile of 27-Mac did not resemble those of the two subtypes. The analysis of the gene expression profiles using single-cell RNA sequencing indicated that 27-Mac clustered differed from other cell types and significantly expressed CD38 and secreted CXCL9 in culture supernatants. These data indicate that 27-Mac is distinct from traditional M2d and provide a new insight into the function of IL-27 and the polarized M2 macrophages.