MicroRNA-21 Deficiency Promotes the Early Th1 Immune Response and Resistance toward Visceral Leishmaniasis

Abstract

MicroRNA-21 (miR-21) inhibits IL-12 expression and impairs the Th1 response necessary for control of Leishmania infection. Recent studies have shown that Leishmania infection induces miR-21 expression in dendritic cells and macrophages, and inhibition of miR-21 restores IL-12 expression. Because miR-21 is known to be expressed due to inflammatory stimuli in a wide range of hematopoietic cells, we investigated the role of miR-21 in regulating immune responses during visceral leishmaniasis (VL) caused by Leishmania donovani infection. We found that miR-21 expression was significantly elevated in dendritic cells, macrophages, inflammatory monocytes, polymorphonuclear neutrophils, and in the spleen and liver tissues after L. donovani infection, concomitant with an increased expression of disease exacerbating IL-6 and STAT3. Bone marrow dendritic cells from miR-21 knockout (miR-21KO) mice showed increased IL-12 production and decreased production of IL-10. On L. donovani infection, miR-21KO mice exhibited significantly greater numbers of IFN-g and TNF-aproducing CD4 + and CD8 + T cells in their organs that was associated with increased production of Th1-associated IFN-g, TNF-a, and NO from the splenocytes. Finally, miR-21KO mice displayed significantly more developing and mature hepatic granulomas leading to reduction in organ parasitic loads compared with wild type counterparts. Similar results were noted in L. donovaniinfected wild type mice after transient miR-21 depletion. These observations indicate that miR-21 plays a critical role in pathogenesis of VL by suppressing IL-12 and Th1associated IFN-g and also inducing disease-promoting induction of the IL-6 and STAT-3 signaling pathway. miR-21 could therefore be used as a potential target for developing host-directed treatment for VL.

miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

“…These miRNAs presented below in sequence are related to activation or modulation of the immune system and may play a crucial role in Leishmania infection either in the control or progression of the infection. The following miRNAs may contribute to the progression of the infection: a) miR-21 seen up-regulated in dendritic cells, macrophages, inflammatory monocytes, polymorphonuclear neutrophils, and in the spleen and liver tissues after L. donovani infection and in splenic leukocytes from L. infantum -naturally infected dogs and related to the inhibition of IL-12 expression and impairment of the Th1 response implied in the control of the infection ( Melo et al., 2019 ; Varikuti et al., 2021 ); b) miR-302a-3p that regulates receptor activator of nuclear factor kappa-B ligand (RANKL) (a member of the tumor necrosis factor TNF superfamily) that regulates T-cell-dependent immune response and apoptosis ( Irwandi et al., 2018 ) and also up-regulated in in vitro L. braziliensis infection ( Souza et al., 2021 ); c) miR-372-3p that inhibits cell proliferation and apoptosis and seen up-regulated in L. braziliensis infection ( Chen et al., 2015 ; Souza et al., 2021 ). Otherwise, distinct miRNAs may act on the control of the infection: a) miR-340-5p that targets the IL-4, major Th2 cytokines secreted by CD4 + T cells, and this miRNA, different from observed with L. infantum , was down-regulated in in vitro L. donovani infection ( Kumar et al., 2020 ); b) miR-302b-3p that inhibits cell proliferation through the AKT pathway by targeting insulin-like growth factor 1 receptor (IGF-1R) ( Guo et al., 2017 ) and was also up-regulated in in vitro L. amazonensis and L. braziliensis infection ( Muxel et al., 2017 ; Souza et al., 2021 ); c) miR-373-3p that is implicated in the regulation of cell proliferation, apoptosis, senescence, migration, and cell invasion and was up-regulated in L. braziliensis infection ( Wei et al., 2015 ; Souza et al., 2021 ).…”

Modulation of microRNAs and claudin-7 in Caco-2 cell line treated with Blastocystis sp., subtype 3 soluble total antigen

“…Focuses on the interaction between parasites and their hosts have pointed out the critical role of host or parasite originated miRNAs in orchestrating the immune responses and pathogenesis of parasites [40][41][42]. Blastocystis sp., is a prevalent protist, which its pathogenicity is still unclear.…”

Necroptosis-mediated HMGB1 secretion of keratinocytes as a key step for inflammation development in contact hypersensitivity

“…Their imbalance results in pathogenesis of many kinds of diseases. TNF-α and IFN-γ are Th1-assocaited cytokines, [ 45 ] and Lauffer et al [ 41 ] reported that lichen planus and lupus erythematosus, both of which present histopathological feature of interface dermatitis, shared the significant transcriptomics characteristics of type I immune response. They found that T cells infiltrating in skin lesions were dominated by TNF-α and IFN-γ positive cells.…”