Candida albicans Activation of Human Monocytes Toward M2 Profile is Reversed by Amphotericin B and Fluconazole

Abstract

Phagocytes, including monocytes/macrophages, play an important role in the host defense during Candida albicans infections. In the L-arginine metabolism, the balance between the activation of two enzymes, inducible Nitric Oxide Synthase (iNOS) and arginase, promotes in the macrophages two alternative metabolic states, while M1 profile is related with host protection, M2 favored the fungal growth and evasion. Our aim was to evaluate the effect of Amphotericin B (AMB) and Fluconazole (FLC) on polarization of human monocytes to M2 profile induced by C. albicans. The human monocytic (Mo) cell line U937 was co-cultured with viable yeast of C. albicans, or Lipopolysaccharides (LPS) or Phorbol-12-myristate-13-acetate (PMA). Nitric Oxide (NO), cytokines production and arginase activity were evaluated. The effect of AMB or FLC on these metabolic pathways in immune cells and on fungus intrinsic arginase activity was studied. C. albicans inhibits NO production in human-monocyte and induces strong host arginase activity (p<0.0001). AMB and FLC inhibited C. albicansinduced arginase activity in immune cells (p<0.001), reaching a percentage of inhibition of 90% for AMB and 78% for FLC. Arginase intrinsic activity of the fungus was blocked by nor-NOHA (arginase inhibitor) and AMB (p<0.05). These results show that C. albicans drives human Mo toward M2 profile and that both antifungal drugs evaluated have the ability to revert C. albicans-induced M2 profile. In a relevant manner, it also provides data about additional effect of AMB as inhibitor of C. albicans endogenous arginase activity. Here in we provide new evidence for the effect of these drugs over the immune cells and the yeast.