Resolvin D1 drives establishment of Leishmania amazonensis infection

Hayna Malta-Santos,Bruno B Andrade,Valéria M Borges,Jaqueline França-Costa,Patrícia T Bozza,Aldina Barral,Dalila L Zanette,Jackson M Costa,Christianne Bandeira-Melo

doi:10.1038/srep46363

Hayna Malta-Santos, Bruno B Andrade + Show 7 more

Open Access

https://doi.org/10.1038/srep46363

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Abstract

Previous studies have indicated that the balance between different eicosanoids reflect the intensity of the inflammatory profile in patients with tegumentary leishmaniasis. More recently, pro-resolution lipid mediators have been shown to play critical roles in dampening pathological inflammatory processes to reestablish homeostasis in a diverse range of experimental settings. Among these lipid mediator, resolvins from D series have been described as potent anti-inflammatory and immunomodulatory mediators, and its activities include inhibition of leukocyte chemotaxis and blockage production of proinflammatory cytokines, while increasing the expression of regulatory mediators. Whether resolvins play significant roles in establishment and persistence of Leishmania infection is currently unknown. We addressed this question in the current study by assessing circulating levels of D-series resolvins in tegumentary leishmaniasis patients presenting with localized or diffuse disease. We found heightened expression of resolvin D1 in diffuse cutaneous leishmaniasis which was correlated with expression profile of biomarkers associated with disease pathogenesis. Additional in vitro experiments using primary human macrophages indicated that resolvin D1 may promote intracellular Leishmania amazonensis replication through a mechanism associated with induction of heme oxygenase-1. These results suggest that targeting resolvin D1 could serve as potential strategy for host directed therapy in diffuse cutaneous leishmaniasis.

Highlights

Resolvins are oxygenated lipid mediators derived from ω-3 polyunsaturated fatty acids that have been associated with resolution of acute inflammation and restoration of tissue homeostasis[1]
These observations suggested that resolvin D1 (RvD1) but not RvD2 may be differentially implicated in the pathogenesis of localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL) and that RvD1 could be associated with the dampened inflammation observed in DCL, which favors Leishmania replication
We show that plasma levels of RvD1, but not of RvD2, were substantially higher in DCL patients compared with that detected in LCL patients

Summary

Introduction

Resolvins are oxygenated lipid mediators derived from ω-3 polyunsaturated fatty acids that have been associated with resolution of acute inflammation and restoration of tissue homeostasis[1]. In the most common clinical form, named localized cutaneous leishmaniasis (LCL), single self-healing skin ulcers are usually observed In this setting, a modest infiltration of macrophages is detected, with very few parasites, due moderate inflammation and cell-mediated immune responses[5]. The role of these three important mediators in Leishmania infection has been further established in experiments using macrophages from mice genetically lacking HO-111, and pharmacological inhibition of arginase-I7 or antibody-mediated blockage of TGF-β12 in infected human macrophages In all these experimental settings, reduction of HO-1, arginase-I and TGF-βresulted in substantial increase in anti-parasite effector mechanisms and production of inflammatory cytokines such as TNF-α, resulting in better control of parasite loads in vitro[7,11,12]. The findings presented here, which still need further validation in different patient populations and epidemiological settings, point to the idea that interfering with the RvD1 pathway could potentially serve as an adjunctive therapy for DCL

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