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

Abstract

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., Ly6C^highCCR2⁺ 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.

Keywords: (L)CL, (localized) cutaneous leishmaniasis; AHR, aryl hydrocarbon receptor; AMP, antimicrobial peptide; Arg, arginase; Arginase; CAMP, cathelicidin-type antimicrobial peptide; CR, complement receptor; DC, dendritic cells; DCL, diffuse cutaneous leishmaniasis; HO-1, heme oxygenase 1; Hypoxia; IDO, indoleamine-2,3-dioxygenase; IFN, interferon; IFNAR, type I IFN (IFN-α/β) receptor; IL, interleukin; Interferon-α/β; Interferon-γ; JAK, Janus kinase; LPG, lipophosphoglycan; LRV1, Leishmania RNA virus 1; Leishmaniasis; Macrophages; Metabolism; NCX1, Na+/Ca2+ exchanger 1; NFAT5, nuclear factor of activated T cells 5; NK cell, natural killer cell; NO, nitric oxide; NOS2 (iNOS), type 2 (or inducible) nitric oxide synthase; NOX2, NADPH oxidase 2 (gp91 or cytochrome b558 β-subunit of Phox); Nitric oxide; OXPHOS, mitochondrial oxidative phosphorylation; PKDL, post kala-azar dermal leishmaniasis; Phagocyte NADPH oxidase; Phox, phagocyte NADPH oxidase; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-beta; TLR, toll-like receptor; Th1 (Th2), type 1 (type2) T helper cell; Tonicity; VL, visceral leishmaniasis; mTOR, mammalian/mechanistic target of rapamycin.

Fig. 1

Schematic overview of macrophage functions in cutaneous leishmaniasis. Most of the functions depicted have been established in the L. major mouse infection model of cutaneous leishmaniasis. For details see the respective sections in the text.

Fig. 2

TNF downregulates Arg1 gene transcription by inhibiting the access of the transcription factor STAT6. IL-4, an alternative macrophage activator, caused tyrosine phosphorylation and nuclear translocation of STAT6, which, together with other transcription factors (not shown), bound to the promoter and enhancer regions regulating the transcription of Arg1 (and other M2 genes; not shown). The binding required prior remodelling and opening of the chromatin, which was associated with IL-4-induced acetylation of lysine 27 of histone 3. Co-stimulation of macrophages with IL-4 plus TNF reduced the histone acetylation and impaired the opening of the gene locus and the binding of phosphorylated STAT6 (Ref. and data not shown).