Abstract
Non-tuberculous mycobacteria (NTM) have been recognized as a causative agent of various human diseases, including severe infections in immunocompromised patients, such as people living with HIV. The most common species identified is the Mycobacterium avium-intracellulare complex (MAI/MAC), accounting for a majority of infections. Despite abundant information detailing the clinical significance of NTM, little is known about host–pathogen interactions in NTM infection. MicroRNAs (miRs) serve as important post-transcriptional regulators of gene expression. Using a microarray profile, we found that the expression of miR-155 and cyclo-oxygenase 2 (COX-2) is significantly increased in bone-marrow-derived macrophages from mice and human monocyte-derived macrophages from healthy volunteers that are infected with NTM. Antagomir against miR-155 effectively suppressed expression of COX-2 and reduced Prostaglandin E2(PGE2) secretion, suggesting that COX-2/PGE2 expression is dependent on miR-155. Mechanistically, we found that inhibition of NF-κB activity significantly reduced miR-155/COX-2 expression in infected macrophages. Most importantly, blockade of COX-2, E-prostanoid receptors (EP2 and EP4) enhanced killing of MAI in macrophages. These findings provide novel mechanistic insights into the role of miR-155/COX-2/PGE2 signalling and suggest that induction of these pathways enhances survival of mycobacteria in macrophages. Defining host–pathogen interactions can lead to novel immunomodulatory therapies for NTM infections which are difficult to treat.
Highlights
MiR-155 Is Upregulated in Bone-Marrow-Derived Macrophages (BMDM) Infected with MAI
To delineate whether the Non-tuberculous mycobacteria (NTM)-induced inflammatory response was regulated by miRNAs, we infected bone-marrow-derived macrophages (BMDM) from wild-type C57
Like murine BMDM, we found that the expression of miR-155 was significantly increased found that the expression of miR-155 was significantly increased in HMDM that were in HMDM that were infected with MAI (Figure 1D)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mycobacterium tuberculosis (MTB) can result in increased expression of cyclooxygenase-2 (COX-2) with production of PGE2, which can modulate the innate immune capacity of the host [17,18,19]. Several miRNAs have shown to play a key regulatory factor in the innate immunity to infections, including MTB [28,29,30,31,32]. MiR-155 expression is increased in MTB-infected macrophages and lungs of mice with. Whether induction of miR-155 and COX-2 can play a role in immune response to NTM infections is not known. We found that expression levels of miR-155 and COX-2 are significantly increased in MAI-infected macrophages. Our data show that infection of macrophages with MAI upregulates miR-155 in an NF-kBdependent manner and is responsible for expression of COX-2 and production of PGE2. Inhibition of COX-2 and the blockade of EP2 and EP4 decreased the survival of NTM in macrophages
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