Journal Article

Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis

Saliba, Alessandra Mattos, Dias-Teixeira, Karina Luiza, Dierckx, Tim, Barral, Aldina Maria Prado, Borges, Valéria Matos, Boaventura, Viviane Sampaio, França-Costa, Jaqueline, Calegari-Silva, Teresa Cristina, Khouri, Ricardo, Fasel, Nicolas, Van Weyenbergh, Johan, Vivarini, Áislan de Carvalho, Lopes, Ulisses Gazos

2017

Overview

parasites infect macrophages, causing a wide spectrum of human diseases, from cutaneous to visceral forms. In search of novel therapeutic targets, we performed comprehensive and mapping of the signaling pathways upstream and downstream of antioxidant transcription factor [nuclear factor erythroid 2-related factor 2 (Nrf2)] in cutaneous leishmaniasis (CL), by combining functional assays in human and murine macrophages with a systems biology analysis of (skin biopsies) CL patient samples. First, we show the PKR pathway controls the expression and activation of Nrf2 in infection . Nrf2 activation also required PI3K/Akt signaling and autophagy mechanisms. Nrf2- or PKR/Akt-deficient macrophages exhibited increased levels of ROS/RNS and reduced expression of Nrf2-dependent gene and reduced parasite load. counteracted the Nrf2 inhibitor Keap1 through the upregulation of p62 PKR. This Nrf2/Keap1 observation was confirmed in skin biopsies from -infected patients. Next, we explored the transcriptome in CL patients, as compared to healthy controls. We found the antioxidant response element/Nrf2 signaling pathway was significantly upregulated in CL, including downstream target p62. enrichment analysis confirmed upstream signaling by interferon and PI3K/Akt, and validated our findings. Our integrated , and approach establish Nrf2 as a central player in human cutaneous leishmaniasis and reveal Nrf2/PKR crosstalk and PI3K/Akt pathways as potential therapeutic targets.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Antioxidants / Autophagy / Biopsy / Biotechnology / Cutaneous leishmaniasis / eIF-2 kinase / Gene expression / Genetic engineering / Immunohistochemistry / Immunology / Kinases / Leishmania / Leukemia / macrophage / Macrophages / NRF2 protein / nuclear factor erythroid 2-related factor 2 / Oxidative stress / Parasites / Parasitic diseases / Phosphorylation / PKR / Potassium / Protease inhibitors / Protein kinase R / Proteins / Protozoa / Signal transduction / Sod1 / Superoxide dismutase / Therapeutic targets / Transcriptomes / Viral infections