| Summary: | MicroRNAs are small non-coding RNAs that regulate cellular processes by the post-transcriptional regulation of gene expression, including immune responses. The shift in the miRNA profiling of murine macrophages infected with <i>Leishmania amazonensis</i> can change inflammatory response and metabolism. L-arginine availability and its conversion into nitric oxide by nitric oxide synthase 2 (<i>Nos</i>2) or ornithine (a polyamine precursor) by arginase 1/2 regulate macrophage microbicidal activity. This work aimed to evaluate the function of miR-294, miR-301b, and miR-410 during early C57BL/6 bone marrow-derived macrophage infection with <i>L. amazonensis</i>. We observed an upregulation of miR-294 and miR-410 at 4 h of infection, but the levels of miR-301b were not modified. This profile was not observed in LPS-stimulated macrophages. We also observed decreased levels of those miRNAs target genes during infection, such as Cationic amino acid transporters 1 (<i>Cat</i>1/<i>Slc</i>7<i>a</i>1), <i>Cat</i>2<i>/Slc</i>7<i>a</i>22 and <i>Nos</i>2; genes were upregulated in LPS stimuli. The functional inhibition of miR-294 led to the upregulation of <i>Cat</i>2 and <i>Tnfa</i> and the dysregulation of <i>Nos</i>2, while miR-410 increased <i>Cat</i>1 levels. miR-294 inhibition reduced the number of amastigotes per infected macrophage, showing a reduction in the parasite growth inside the macrophage. These data identified miR-294 and miR-410 biomarkers for a potential regulator in the inflammatory profiles of microphages mediated by <i>L. amazonensis</i> infection. This research provides novel insights into immune dysfunction contributing to infection outcomes and suggests the use of the antagomiRs/inhibitors of miR-294 and miR-410 as new therapeutic strategies to modulate inflammation and to decrease parasitism.
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