New Therapeutic Tools to Shape Monocyte Functional Phenotypes in Leishmaniasis

Abstract

In the innate immunity to Leishmania infection tissue-resident macrophages and inflammatory monocytes accumulate host-cell, effector, and efferocytosis functions. In addition, neutrophils, as host, effector, and apoptotic cells, as well as tissue-resident and monocyte-derived dendritic cells (DCs) imprint innate and adaptive immunity to Leishmania parasites. Macrophages develop phenotypes ranging from antimicrobial M1 to parasite-permissive M2, depending on mouse strain, Leishmania species, and T-cell cytokines. The Th1 (IFN-γ) and Th2 (IL-4) cytokines, which induce classically-activated (M1) or alternatively-activated (M2) macrophages, underlie resistance versus susceptibility to leishmaniasis. While macrophage phenotypes have been well discussed, new developments addressed the monocyte functional phenotypes in Leishmania infection. Here, we will emphasize the role of inflammatory monocytes to access how potential host-directed therapies for leishmaniasis, such as all-trans-retinoic acid (ATRA) and the ligand of Receptor Activator of Nuclear Factor-Kappa B (RANKL) might modulate immunity to Leishmania infection, by directly targeting monocytes to develop M1 or M2 phenotypes.

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

“…Moreover, treatment with Mer-Ig upregulated M1 responses in cocultured BMDMs from T. cruzi-resistant (Th1-prone) B6 and T. cruzi-susceptible (Th2prone) BALB/c mice. Whereas susceptibility and resistance to intracellular protozoan parasites are related to various features of both innate and adaptative immunity in these particular mouse strains 3,45 , efferocytosis-mediated suppression of macrophage responses may also promote parasite infection. For instance, our results that show improved M1 responses with the use of the TAM inhibitor corroborate the role of TAM receptors in L. major infection, where Axl −/− Mer −/− (double KO) mice showed increased innate responses of dermal macrophages 39 .…”

Field-Deployable Treatments For Leishmaniasis: Intrinsic Challenges, Recent Developments and Next Steps

“…More importantly, the use of a drug available in more than 100 countries worldwide such as enalapril 159 would be an ideal and affordable treatment to be deployed in the field in Leishmania- endemic areas. It is important to keep in mind that the profile and activation of iMOs differ among Leishmania species and mouse strain, 160 so further therapeutic target studies must be specifically designed against different clinical manifestations of leishmaniasis. Still, immunomodulatory therapies directly targeting iMOs could facilitate the immune phenotype necessary to eliminate intracellular parasites.…”

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis

“…Similar paradox exists in miR-155 functions as well. On the one hand, miR-155 promotes M1 polarization while preventing M2 polarization and facilitates Leishmania elimination [ 3 , 37 , 42 ]; on the other hand, miR-155 promotes Leishmania persistence via inhibition of macrophage apoptosis [ 43 ]. Thus, a balanced miR-155 expression within macrophages needs to maintain M1 macrophage polarization without repressing apoptosis.…”

“…Macrophages play dual roles in many infectious diseases: playing host to an intracellular pathogen such as Leishmania or acting as an executioner eliminating the pathogen by eliciting antileishmanial immune effectors such as cytokines [ 1 , 2 ]. Thus, macrophages can be polarized to host-protective (M1 macrophages) or proparasitic phenotype (M2 macrophages) [ 3 ]. Macrophages are the major producers of IL-1β, IL-6, IL-12, IL-10, and IL-23 [ 4 ].…”