TY - JOUR
T1 - MicroRNA-155 modulates macrophages’ response to non-tuberculous mycobacteria through COX-2/PGE2 signaling
AU - Yuan, Zhihong
AU - Prasla, Zohra
AU - Lee, Frances Eun Hyung
AU - Bedi, Brahmchetna
AU - Sutliff, Roy L.
AU - Sadikot, Ruxana T.
N1 - Funding Information:
This work was funded by Merit Review Award 5I01BX001786 to RTS, R01. HL144478 to RTS and CF Foundation Grant to RTS.
Publisher Copyright:
© 2021 by the authors.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - COX-2
KW - MiR-155
KW - Mycobacterium avium
KW - Non-tuberculous mycobacteria
KW - PGE2
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U2 - 10.3390/pathogens10080920
DO - 10.3390/pathogens10080920
M3 - Article
C2 - 34451384
AN - SCOPUS:85111643834
SN - 2076-0817
VL - 10
JO - Pathogens
JF - Pathogens
IS - 8
M1 - 920
ER -