Macrophages as host, effector and immunoregulatory cells in leishmaniasis: Impact of tissue micro-environment and metabolism.

Leishmania are protozoan parasites that predominantly reside in myeloid cells within their mammalian hosts. Monocytes and macrophages play a central role in the pathogenesis of all forms of leishmaniasis, including cutaneous and visceral leishmaniasis. The present review will highlight the diverse roles of macrophages in leishmaniasis as initial replicative niche, antimicrobial effectors, immunoregulators and as safe hideaway for parasites persisting after clinical cure. These multiplex activities are either ascribed to defined subpopulations of macrophages (e.g., Ly6Chigh CCR2+ inflammatory monocytes/monocyte-derived dendritic cells) or result from different activation statuses of tissue macrophages (e.g., macrophages carrying markers of of classical [M1] or alternative activation [M2]). The latter are shaped by immune- and stromal cell-derived cytokines (e.g., IFN-γ, IL-4, IL-10, TGF-β), micro milieu factors (e.g., hypoxia, tonicity, amino acid availability), host cell-derived enzymes, secretory products and metabolites (e.g., heme oxygenase-1, arginase 1, indoleamine 2,3-dioxygenase, NOS2/NO, NOX2/ROS, lipids) as well as by parasite products (e.g., leishmanolysin/gp63, lipophosphoglycan). Exciting avenues of current research address the transcriptional, epigenetic and translational reprogramming of macrophages in a Leishmania species- and tissue context-dependent manner.