Abstract
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 Leishmania amazonensis can change inflammatory response and metabolism. L-arginine availability and its conversion into nitric oxide by nitric oxide synthase 2 (Nos2) 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 L. amazonensis. 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 (Cat1/Slc7a1), Cat2/Slc7a22 and Nos2; genes were upregulated in LPS stimuli. The functional inhibition of miR-294 led to the upregulation of Cat2 and Tnfa and the dysregulation of Nos2, while miR-410 increased Cat1 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 L. amazonensis 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.
Highlights
IntroductionMicroRNAs (miRNAs) are small non-coding RNAs with 18–25 nucleotides that mediate the post-transcriptional regulation of the genes involved in physiological and pathological conditions, including the inflammatory response [1,2]. miRNAs are transcribed from intergenic, exonic, or intronic regions by the RNA polymerase II and are processed into primary miRNA transcripts (pri-miRNA), and they subsequently enter the precursor (premiRNA) and mature form across a series of steps involving class 2 RNAse III DROSHA andDicer [3,4]. miRNAs recognize the complementary sequences in the 30 untranslated regions (30 UTR) of given transcripts, which cause their degradation or translational repression [3,4].miRNA dysregulation occurs through various mechanisms, encompassing perturbations of miRNA transcription, epigenetic mechanisms, and disruption of the miRNA synthesis machinery [5].Different miRNA expressions display macrophage polarization during infection, affecting the macrophage activation and the polarization to classically characterized M1-proinflammatory or M2-anti-inflammatory/pro-resolution phenotype [6]
We showed that miR-294 expression was independent of Toll-like receptor (TLR)-2, TLR-4, or MyD88 in C57BL/6Jmacrophages infected with L. amazonensis [28]
To understand the impact of with L. amazonensis promotes alterations to this scenario, leading to an M2-like macrophage miRNAs on L-arginine metabolism in C57BL/6 macrophages, we focused on the analysis phenotype in the early stages of infection [34]
Summary
MicroRNAs (miRNAs) are small non-coding RNAs with 18–25 nucleotides that mediate the post-transcriptional regulation of the genes involved in physiological and pathological conditions, including the inflammatory response [1,2]. miRNAs are transcribed from intergenic, exonic, or intronic regions by the RNA polymerase II and are processed into primary miRNA transcripts (pri-miRNA), and they subsequently enter the precursor (premiRNA) and mature form across a series of steps involving class 2 RNAse III DROSHA andDicer [3,4]. miRNAs recognize the complementary sequences in the 30 untranslated regions (30 UTR) of given transcripts, which cause their degradation or translational repression [3,4].miRNA dysregulation occurs through various mechanisms, encompassing perturbations of miRNA transcription, epigenetic mechanisms, and disruption of the miRNA synthesis machinery [5].Different miRNA expressions display macrophage polarization during infection, affecting the macrophage activation and the polarization to classically characterized M1-proinflammatory or M2-anti-inflammatory/pro-resolution phenotype [6]. The host’s immune response uses this amino acid to produce NO, leading to parasite clearance [17,18]. In this case, the amino acid used can indicate how the macrophages polarize on the M1/M2 dichotomy [14,19]. The amino acid used can indicate how the macrophages polarize on the M1/M2 dichotomy [14,19] In this scenario, miRNAs can act as regulators of how the cells decide to use the amino acid
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
