MiRNA Exporter HuR Clears Macrophage Internalized Pathogens by Promoting Pro-inflammatory Response

miRNA derepressor protein HuR can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. We have identified how HuR, by inducing extracellular vesicles-mediated export of miRNAs, ensures robust derepression of miRNA-repressed cytokines essential for strong pro-inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of visceral leishmaniasis, on the contrary alters immune response of the host macrophage by a variety of complex mechanisms to promote anti-inflammatory response-essential for its survival. We have found that during Leishmania infection, the pathogen targets HuR to promote onset of anti-inflammatory response in mammalian macrophages. In infected macrophages, Leishmania also upregulate Protein Phosphatase 2A that acts on Ago2 protein to keep it in dephosphorylated and miRNA associated form. This causes robust repression of the miRNA-targeted pro-inflammatory cytokines to establish an anti-inflammatory response in infected macrophages. HuR has an inhibitory effect on Protein Phosphates 2A expression and mathematical modelling of macrophage activation process supports antagonistic miRNA-modulatory roles of HuR and Protein Phosphatase 2A which mutually balances immune response in macrophage by targeting miRNA function.