Fig 1.
A basic macrophage-T cell subset differentiation scheme that counteractively regulates the alternative outcomes of Leishmania infection.
Macrophages are the host cells for the protozoan parasite Leishmania (PV with amastigotes are shown in green). The top half (above the broken line) shows the condition when Th1 and Th17 cells are differentiated in presence of the respective signature transcription factors T-bet and ROR-γt. These cells activate macrophages to induce iNOS but to reduce arginase (Arg1). iNOS catalyzes the formation of nitric oxide that kills the amastigotes within macrophages. The bottom half shows the differentiation of Th2 ad Treg cells in presence of the respective signature transcription factors GATA-3 and FOXP3. IL-4 and IL-10 secreted by these cells deactivate macrophages to reduce iNOS, but increase Arg1, expression resulting in parasite growth in macrophages. miRs target these macrophage–T cell interactions to manipulate the outcomes of Leishmania infection. iNOS, inducible nitric oxide synthase; PV, parasitophorous vacuole.
Fig 2.
Leishmania-expressed ligands such as LPG interact with corresponding receptors (e.g., TLR2 for LPG) on macrophages and signal altered miRNA expression (at the centre of the figure).
As shown clockwise surrounding the central macrophage, these miRNAs affect macrophage production of proinflammatory and anti-inflammatory cytokines, antigen processing and presentation of macrophages, CD4+ T cell polarization into opposing effector subsets, antileishmanial or proleishmanial effects, and macrophage apoptosis or survival. Proleishmanial to antileishmanial functions are induced by the Th1 cell secreted IFN-γ and TNF-α. A balance between these counteractive functions regulated by miRNAs, which can be altered by Leishmania, determines the outcome of the infection. The Leishmania-infected macrophages secrete exosomes filled with different antigens and miRs. The exosomes can be taken up by the neighboring uninfected macrophages, wherein these miRs can execute their functions. The key to the cytokines are shown on the upper right corner of the figure. LPG, lipophosphoglycan; miRNA, microRNA.
Fig 3.
TGF-β induced by Leishmania infection binds to TGF-β receptor causing its phosphorylation and subsequent SMAD2/SMAD3-dependent transcriptional and posttranscriptional regulation of miRNA expression in macrophages.
These miRNAs make complexes with the target mRNAs—one miRNA binding to many mRNAs—to destabilize or suppress mRNAs translation. Depending on the miRNAs up-regulated or down-regulated, proleishmanial or antileishmanial effects are observed. miRNA, microRNA.
Fig 4.
HuR and Phosphatases reciprocally regulate proinflammatory and anti-inflammatory cytokines.
While Protein Phosphatase 2A (PP2A) increases miRNA activity, HuR overexpression down-regulates PP2A activation, and thereby miRNA expression, leading to increased proinflammatory cytokines. Leishmania-derived protease Gp-63 degrades HuR making active PP2A available for enhancing anti-inflammatory cytokines. On the other hand, Leishmania-derived LPG may activate TLRs to regulate PP2A activation that through regulation of argonaute proteins modulates cytokine response. LPG, lipophosphoglycan; miRNA, microRNA.
Fig 5.
miRNA regulation of Leishmania infection.
TGF-β, and perhaps other cytokines too, regulate miRNA expression in macrophages. As Leishmania infection renders the intracellular environment hypoxic, the HIF-1α induces miR210 to enhance IL-10 production but reduce NF-κB activation and TNF-αR expression to enhance parasite load in the parasitophorous vacuoles in macrophages. Various miRNAs expressed during Leishmania infection modulate cellular processes including cytokine signaling that affects the outcome of Leishmania infection. Similarly, 2 counteractive sets of miRs reciprocally regulate M1 and M2 macrophage subsets differentiation that affects parasite growth. The other miRs regulate macrophage Autophagy and apoptosis and IFN-γR signaling to alter intracellular amastigote numbers. The available literature is too diverse in terms of Leishmania species, macrophage populations, experimental models, and assays to derive a coherent and integrative view of miRs role in Leishmania infection. Therefore, only a fraction of the literature is used to develop the current perspective. HIF-1α, hypoxia-inducible factor-1α; miRNA, microRNA.