Perturbed microRNA Expression by Mycobacterium tuberculosis Promotes Macrophage Polarization Leading to Pro-survival Foam Cell

Abstract

Tuberculosis (TB) is one of the prevalent causes of death worldwide, with 95% of these deaths occurring in developing countries, like India. The causative agent, Mycobacterium tuberculosis (MTb) has the tenacious ability to circumvent the host’s immune system for its own advantage. Macrophages are one of the phagocytic cells that are central to immunity against MTb. These are highly plastic cells dependent on the milieu and can showcase M1/M2 polarization. M1 macrophages are bactericidal in action, but M2 macrophages are anti-inflammatory in their immune response. This computational study is an effort to elucidate the role of miRNAs that influences the survival of MTb in the macrophage. To identify the miRNAs against critical transcription factors, we selected only conserved hits from TargetScan database. Further, validation of these miRNAs was achieved using four databases viz. DIANA-microT, miRDB, miRanda-mirSVR, and miRNAMap. All miRNAs were identified through a conserved seed sequence against the 3′-UTR of transcription factors. This bioinformatics study found that miR-27a and miR-27b has a putative binding site at 3′-UTR of IRF4, and miR-302c against IRF5. miR-155, miR-132, and miR-455-5p are predicted microRNAs against suppressor of cytokine signaling transcription factors. Several other microRNAs, which have an affinity for critical transcription factors, are also predicted in this study. This MTb-associated modulation of microRNAs to modify the expression of the target gene(s) plays a critical role in TB pathogenesis. Other than M1/M2 plasticity, MTb has the ability to convert macrophage into foam cells that are rich in lipids and cholesterol. We have highlighted few microRNAs which overlap between M2/foam cell continuums. miR-155, miR-33, miR-27a, and miR-27b plays a dual role in deciding macrophage polarity and its conversion to foam cells. This study shows a glimpse of microRNAs which can be modulated by MTb not only to prevent its elimination but also to promote its survival.

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…[146][147] There is emerging evidence that miRNAs could serve as cancer immunotherapy and could serve as therapeutic targets in TB. [148][149] Cytokines and proteases TNF-α is essential to granuloma integrity, macrophage antimicrobial activity and ROSmediated Mtb killing.…”

ADAR1 attenuates allogeneic graft rejection by suppressing miR‐21 biogenesis in macrophages and promoting M2 polarization

“…**P , 0.01. polarization (42). Ahluwalia et al (43) found that Mycobacterium tuberculosis can affect miR-155, miR-33, miR-27a, and miR-27b, all of which play dual roles in determining macrophage polarization and transformation to foam cells. During the development of schistosomiasis, significant up-regulation of miR-146a/b was reported in macrophages, which promoted the polarization of IFN-g-induced macrophages into M1 by targeting signal transducer and activator of transcription 1 (44).…”

MiRNA-494 enhances M1 macrophage polarization via Nrdp1 in ICH mice model

“…Various studies have identified miRNA expression profiles in M1 and M2 polarized macrophages. More specifically, miR-9, miR-127, miR-155, and miR-125b have been reported to promote M1 polarization while miR-494, miR-223, miR-34a and let-7c can induce M2 polarization in macrophages [37]. Therefore, miRNAs that regulate macrophage polarization may have therapeutic potential in immunerelated diseases.…”