| Summary: | <i>Leishmania</i> infection of phagocytic cells, such as macrophages, induces the differentiation of infected cells into different phenotypes according to their surrounding microenvironments. The classical activation of macrophages involves metabolic reprogramming, in which several metabolites such as succinate, fumarate and itaconate are accumulated. The immunoregulatory functions of itaconate in the context of <i>Leishmania</i> infection were investigated in this paper. Ex vivo bone marrow-derived macrophages were differentiated into classically activated macrophages through IFNG activation and infection with <i>Leishmania infantum</i>. A high-throughput real-time qPCR experiment was designed for the analyses of 223 genes involved in immune response and metabolism. The transcriptional profile of classically activated macrophages revealed the enrichment of the IFNG response pathways and the upregulation of genes such as <i>Cxcl9</i>, <i>Irf1</i>, <i>Acod1</i>, <i>Il12b</i>, <i>Il12rb1</i>, <i>Nos2</i> or <i>Stat1</i>. In vitro pre-stimulation with itaconate induced a loss of the parasite control and the upregulation of genes related to local acute inflammatory response. Our results reveal that itaconate accumulation dampened classically activated macrophage antiparasitic activity, and this is reflected by the differential expression of the <i>Il12b</i>, <i>Icosl</i> and <i>Mki67</i> genes. The possibility of inducing parasite-killing responses in the host through metabolic reprograming is an interesting approach for the treatment of <i>Leishmania</i> infections that will undoubtedly attract increasing attention in the coming years.
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