Targeting and activation of macrophages in leishmaniasis. A focus on iron oxide nanoparticles

Abstract

Macrophages play a pivotal role as host cells for Leishmania parasites, displaying a notable functional adaptability ranging from the proinflammatory, leishmanicidal M1 phenotype to the anti-inflammatory, parasite-permissive M2 phenotype. While macrophages can potentially eradicate amastigotes through appropriate activation, Leishmania employs diverse strategies to thwart this activation and redirect macrophages toward an M2 phenotype, facilitating its survival and replication. Additionally, a competition for iron between the two entities exits, as iron is vital for both and is also implicated in macrophage defensive oxidative mechanisms and modulation of their phenotype. This review explores the intricate interplay between macrophages, Leishmania, and iron. We focus the attention on the potential of iron oxide nanoparticles (IONPs) as a sort of immunotherapy to treat some leishmaniasis forms by reprogramming Leishmania-permissive M2 macrophages into antimicrobial M1 macrophages. Through the specific targeting of iron in macrophages, the use of IONPs emerges as a promising strategy to finely tune the parasite-host interaction, endowing macrophages with an augmented antimicrobial arsenal capable of efficiently eliminating these intrusive microbes.

Keywords: host-directed therapies; iron oxide nanoparticles; leishmania; macrophages; target; targeted delivery.

Figure 1

Oxidative response in Leishmania infection. The key leishmanicidal molecules produced by the macrophage are ROS and NO, although Leishmania parasite attempts to stop their generation at different levels. On the one hand, Leishmania can inhibit iNOS expression through multiple mechanisms, including JAK2-STAT1 and ERK1/2-AP1 signaling pathways interference, chromatin condensation through HDAC1 recruitment, negative regulation by microRNAs, and substrate competition through overexpression of the enzyme arginase. In the case of ROS, the parasite prevents Nox2 complex formation and PKC activation and induces mitochondrial UCP2. Actions that Leishmania triggers to counteract the production of ROS/NO by the host cell are indicated in red. Figure created with biorender.com.

Figure 2

Leishmania parasites evading immune surveillance. Leishmania reduces antigenic presentation by preventing Major Histocompatibility Complex-II (MHCII) clusters formation by modifying membrane fluidity and inducing their protease-mediated degradation. In addition, the parasite induces proteases to degrade the transcription factor NF-kB, which is essential for the expression of pro-inflammatory cytokines. Figure created with biorender.com.

Figure 3

Leishmania and macrophage apoptosis. Macrophages activate the self-destruct mechanism in response to DNA fragmentation because of the infective process, and the parasite then implements strategies to inhibit this process. These include upregulation of DNA repair enzymes, activation of the PI3K/Akt pathway to prevent the release of cytochrome C (Cyt C) and promotion of anti-apoptotic proteins such as Bcl-2 and the inhibition of pro-apoptotic proteins such as Bad/Bax. Actions that Leishmania triggers to counteract the apoptotic process are presented in red. Figure created with biorender.com.

Figure 4

Biodistribution of NPs and encounter with Leishmania-infected macrophages. After their intravenous administration, NPs in general tend to accumulate in the macrophages of organs with fenestrated vasculature such as liver, spleen and bone marrow, also the major Leishmania hosts in VL. Only a small fraction of long-circulating NPs will get Leishmania-infected skin lesions. After topical administration and even in damaged skin, very small NPs have poor chance of arriving the dermal infected macrophages, making mandatory their intralesional (and uncomfortable) administration. Figure created with biorender.com.

Figure 5

Effect of IONPs on macrophages. Interaction of IONPs with TLR4 initiates the activation of IRF5 and several MAPKs culminating in the expression of inflammatory response genes. In addition, IONPs are internalized by macrophages and are biodegraded in the phagolysosome resulting in the release of iron cations into the cytosol. This free iron induces ROS production by the Fenton reaction; and modulates protein activity by acting as a cofactor, and protein expression by the IRE system. All this converges in the induction of an M1 profile in the macrophage. Figure created with biorender.com.

Figure 6

Scheme of immune profiles of the main clinical manifestations of leishmaniasis and suitability of IONPs. The balance between Th and macrophage responses highlights the suitability of IONP as a potential therapeutic strategy for VL, MCL, and PKDL, where macrophage abundance and/or pronounced T-Regulatory response are prominent features. DCL,Diffuse Cutaneous Leishmaniasis; PKDL, Post-Kala-Azar Dermal Leishmaniasis; VL, Visceral Leishmaniasis; LCL, Localized Cutaneous Leishmaniasis; MCL, Mucocutaneous Leishmaniasis. Figure created with biorender.com.