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Parasite recognition by Toll-like receptors (TLRs) contributes to macrophage activation and subsequent control of  Leishmania  infection through the coordinated production of pro-inflammatory and microbicidal effector molecules. The modulation of microRNA (miRNA) expression by  Leishmania  infection potentially mediates the post-transcriptional regulation of the expression of genes involved in leishmanicidal activity. Here, the contribution of TLR signaling to the miRNA profile and gene expression was evaluated in  Leishmania amazonensis -infected murine macrophages. The infectivity of  L. amazonensis  was higher in murine bone marrow-derived macrophages from mice knockout for myeloid differentiation factor 88 (MyD88 −/− ), TLR2 (TLR2 −/− ), or TLR4 (TLR4 −/− ) than wild type C57BL/6 (WT).  L. amazonensis  infection of WT macrophages modulated the expression of 32% of the miRNAs analyzed, while 50% were upregulated. The absence of MyD88, TLR2, and TLR4 altered the percentage of miRNAs modulated during  L. amazonensis  infection, including the downregulation of let-7e expression. Moreover, the absence of signals mediated by MyD88, TLR2, or TLR4 reduced nitric oxide synthase 2 ( No s2) mRNA expression during infection. Indeed, the inhibition of let-7e increased levels of the  Nos 2 mRNA and NOS2 (or iNOS) protein and nitric oxide (NO) production in  L. amazonensis -infected macrophages (4–24 h). The absence of TLR2 and inhibition of let-7e increased the expression of the arginase 1 ( Arg 1) mRNA but did not alter the protein level during infection. However, higher levels of the L-arginine transporters  Cat 2B and  Cat 1 were detected in the absence of Myd88 signaling during infection but were not altered following let-7e inhibition. The inhibition of let-7e impacted the global expression of genes in the TLR pathway by upregulating the expression of recognition and adaptors molecules, such as  Tlr 6,  Tlr 9,  Ly 96,  Tirap, Traf  6,  Ticam 1,  Tollip, Casp 8,  Map 3 k 1,  Mapk 8,  Nfkbib, Nfkbil 1,  Ppara, Mapk8i p3,  Hspd 1, and  Ube2 n, as well as immunomodulators, such as  Ptgs 2/ Cox 2,  Csf  2,  Csf  3,  Ifnb 1,  Il 6 ra , and  Ilr 1, impacting NOS2 expression, NO production and parasite infectiveness. In conclusion,  L. amazonensis  infection alters the TLR signaling pathways by modulating the expression of miRNAs in macrophages to subvert the host immune responses.

Toll-Like Receptor and miRNA-let-7e Expression Alter the Inflammatory Response in Leishmania amazonensis-Infected Macrophages