miRNA-mediated regulation of c-Maf, Bach-1, and Elmo-1 in Mtb-infected M(IL-4/IL-13) macrophages
Macrophage activation in hosts can be skewed to a less microbicidal alternative activated state by Mycobacterium tuberculosis (Mtb) to avoid classical effector killing functions. The Division of Immunology team investigated whether the molecular basis of this evasion mechanism could uncover potential candidates for host directed therapy against tuberculosis (TB).
The study identified miR-143 and miR-365 which were highly up-regulated in Mtb-infected M(IL-4/IL-13) polarized macrophages. Knockdown of miR-143 and miR-365 decreased mycobacterial burden and significantly reduced the release of chemokine CCL5 and pro-inflammatory cytokine IL-6 in M(IL-4/IL-13) polarized macrophages. The group then validated c-Maf, Bach-1 and Elmo-1 as potential target genes for both miRNAs and demonstrated that miR-143 and miR-365 functions are mediated at least partially through interaction with c-Maf, Bach-1, and Elmo-1. The data therefore suggests miR-143 and miR-365 upregulation plays a host-detrimental role during Mtb infection of M(IL-4/IL-13) macrophages, and showcases for the first time that the activities of miR-143 and miR-365 are mediated by the direct targeting of c-Maf, Bach-1 and Elmo-1 in Mtb-infected M(IL-4/IL-13) macrophage.
In summary, the research shows that miR-143 and miR-365 play a host detrimental role during Mtb infection and highlights the role and miRNA-mediated regulation of c-Maf, Bach-1, and Elmo-1 in Mtb-infected M(IL-4/IL-13) macrophages. The authors urged further study to investigate miRNAs and target genes as potential candidates for host directed TB therapy.
Co-authors for the paper from the Division of Immunology and the Institute of Infectious Diseases and Molecular Medicine were Ousman Tamgue, Lorna Gcanga, Mumin Ozturk, Lauren Whitehead, Shandre Pillay, Raygaana Jacobs, Frank Brombacher and Reto Guler.
Article by Bonamy Holtak