Abstract
Macrophage–Leishmania interactions are central to parasite growth and disease outcome. Macrophages have developed various strategies to fight invaders, including oxidative burst. While some microorganisms seem to survive and even thrive in an oxidative environment, others are susceptible and get killed. To counter oxidative stress, macrophages switch the expressions of cytoprotective and detoxifying enzymes, which are downstream targets of the nuclear factor erythroid 2-related factor 2 (Nrf2), to enhance cell survival. We have explored the transcription of NRF2 and of its target genes and compared the effect of the parasite on their transcription in bone marrow-derived macrophages (BMdMs) from Leishmania-resistant and Leishmania-susceptible mice. While heme oxygenase 1 (HO-1) transcription is independent of the genetic background, the transcription of glutathione reductase (Gsr) and of cysteine/glutamate exchange transporter (Slc7a11), involved in glutathione accumulation, was differentially regulated in BMdMs from both mouse strains. We also show that, except for HO-1, known to favor the survival of the parasite, the transcription of the selected genes, including Gsr, CD36, and catalase (CAT), was actively repressed, if not at all time points at least at the later ones, by the parasite, especially in Balb/c BMdMs. Consistent with these results, we found that the silencing of NRF2 in this study increases the survival and multiplication of the parasite.
Highlights
Leishmaniasis is a parasitic disease caused by the protozoa Leishmania
Because the expressions of antioxidant genes are under the control of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor (TF), the activation of this master TF was investigated
At 3 hpi, the Nrf2 protein started to be exported to the nucleus, and the nuclear localization of NRF2 was observed until 12 hpi (Figure 2C)
Summary
Leishmaniasis is a parasitic disease caused by the protozoa Leishmania. This disease is spread worldwide and causes different clinical manifestations ranging from cutaneous lesions healing spontaneously to visceral leishmaniasis, which is the most serious form of the disease that is fatal in the absence of treatment. Macrophages encounter Leishmania by employing an array of directly antimicrobial mechanisms such as the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are highly destructive to Leishmania These oxidant compounds, while crucial in clearing invading pathogens, may cause oxidative damage to the host cells. Cells have developed different antioxidant defense systems to counter oxidative stress These include the thioredoxin (Trx) and glutathione (GSH) systems, the two major thiol-dependent antioxidant mechanisms in cells, and heme oxygenase 1 (HO1), which catalyzes the rate-limiting step of heme oxidation to biliverdin, carbon monoxide, and free ferrous iron (Tonelli et al, 2018). Most of these cytoprotective and detoxifying enzymes that enhance cell survival are downstream targets of the nuclear factor erythroid 2-related factor 2 (Nrf2)
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