Secreted Cyclophilin A Induces M1 and M2 Macrophage Polarization in the THP-1 Model in vitro

Fate of monocytes that migrate into tissues is determined by various mediators at the site of inflammation. The microenvironment governs monocyte differentiation and polarization into macrophages, which acquire different surface markers and opposite functions. Secreted cyclophilin A (CypA) is a pro-inflammatory factor and a component of the monocyte humoral microenvironment. In these studies, effects of recombinant human CypA (rhCypA) on differentiation of human monocytic cells were evaluated in the THP-1 in vitro model. RhCypA induced polarization of M1 macrophages in the early stages of THP-1 ontogenesis without additional stimuli, whereas it promoted M2 polarization only in the cells differentiated to M0 monocytes and in the presence of IL-4 and IL-13. Under conditions of M2 induction, rhCypA significantly upregulated expression of the genes of characteristic M2 markers CD163 and IL-10 in the THP-1 cells, and decreased the level of p38 MAP kinase activation, suggesting diminished pro-inflammatory activity of the generated cells. The RhCypA-induced M1 and M2 macrophages inhibited proliferation of activated CD4+ T cells via direct cell-cell contact. These findings suggested that secreted CypA could induce generation of suppressor M2 macrophages and/or myeloid-derived suppressor cells at the site of inflammation during infection or cancer progression. This new immunoregulatory effect of rhCypA could be of particular clinical relevance for the development of strategies for controlling chronic inflammation and reprogramming the tumor microenvironment.