Tomozumi Imamichi, Jun Yang, Qian Chen, Suranjana Goswami, Mayra Marquez, Udeshika Kariyawasam, Homa Nath Sharma, Rosana Wiscovitch-Russo, Xuan Li, Akihiro Aioi, Joseph W Adelsberger, Weizhong Chang, Jeanette Higgins, Hongyan Sui Laboratory of Basic Research,
Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research
Laboratory of Basic Research, SEPTEM-SOKEN Co., Ltd.,
AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research

[Abstract]
Interleukin (IL)-27 is an anti-viral cytokine. IL-27-treated monocyte-derived macrophages (27-Mac) suppressed HIV replication. Macrophages are generally divided into two subtypes, M1 and M2 macrophages. M2 macrophages can be polarized into M2a, M2b, M2c, and M2d by various stimuli. IL-6 and adenosine induce M2d macrophages. 27-Mac was considered M2d macrophages. In the current study, we compared biological function and gene expression profiles between 27-Mac and M2d subtypes.
Mac and BAY60-658-polarized M2d (BAY-M2d) resisted HIV infection, but IL-6-polarized M2d (6-M2d) lacked the anti-viral effect. Although phagocytosis activity was comparable among the three macrophages, only 27-Mac, but neither 6-M2d nor BAY-M2d, enhanced the generation of ROS. The cytokine-producing profile of 27-Mac did not resemble that of the two subtypes. The scRNA-seq revealed that 27-Mac exhibited a different clustering pattern compared to other M2ds, and each 27-Mac expressed a distinct combination of anti-viral genes. Furthermore, 27-Mac did not express the biomarkers of M2a, M2b, and M2c. However, it significantly expressed CD38 (p<0.01) and secreted CXCL9 (p<0.001), which are biomarkers of M1.
These data suggest that 27-Mac may be classified as either an M1-like subtype or a novel subset of M2, which resists HIV infection mediated by a different mechanism in individual cells using different anti-viral gene products. Our results provide a new insight into the function of IL-27 and macrophages.