CircAGFG1modulates autophagy and apoptosis of macrophages infected by Mycobacterium tuberculosis via the Notch signaling pathway

Abstract

Background: Recent studies have revealed the involvement of circular RNAs (circRNAs) in the control and elimination of invading Mycobacterium tuberculosis (Mtb) by macrophages. However, the regulatory mechanism of circAGFG1 in macrophages infected by Mtb has not been fully explored. In this study, we sought to investigate the role of circAGFG1 on autophagy and apoptosis of Mtb-infected macrophages and reveal its the molecular mechanism. Methods: The expression of circAGFG1 in macrophages from patients with active tuberculosis and inMtb-treated macrophages in vitro was explored. Then, the effect of circAGFG1 on autophagy and apoptosis of Mtb-infected macrophages was evaluated by flow cytometry, electron microscope, immunofluorescence, and Western blotting. Bioinformatics analysis was used to identify and validate the downstream regulatory pathway of circAGFG1, miRNA-1257/Notch. For further analysis, the role of miRNA-1257 on autophagy and apoptosis was assessed.Results: In vitro, ectopic expression of circAGFG1 upregulated autophagy and reduced apoptosis significantly in Mtb-infected cells. Notch levels were discovered to be increased by the silencing effect of circAGFG1 on miRNA-1257 expression. miRNA-1257 was found to noticeably reduce autophagy and promote macrophage apoptosis. Increased circAGFG1 expression, decreased monocyte apoptosis, and enhanced autophagy were found in macrophages from patients with active tuberculosis. Conclusions:In active tuberculosis, circAGFG1 enhances autophagy and reduces apoptosis via the miRNA-1257/Notch axis; this provides new therapeutic targets for tuberculosis patients.

Shedding Light on Autophagy During Human Tuberculosis. A Long Way to Go

“…Moreover, the expression of this miRNA decreased upon anti-TB treatment ( Chen Z. et al., 2015 ). Besides, circAGFG1 was found to upregulate autophagy in Mtb –infected alveolar macrophages by targeting miRNA-1257, which in turn suppresses Notch signaling pathway ( Shi et al., 2020 ).…”

The Roles of Host Noncoding RNAs in Mycobacterium tuberculosis Infection

“…Liu et al found that circRNA_051239 was significantly upregulated in drug-resistant TB patients, and circRNA_051239 may act as sponges of miR-320a and play a crucial role in the development of TB drug resistance (77,78). Moreover, circAGFG1 can enhance autophagy and reduce the rate of apoptosis, which is achieved by targeting miRNA1257 to regulate Notch signaling in the macrophages infected by M. tuberculosis (79). Another study indicated that in the macrophages infected by M. tuberculosis, the overexpression circRNA-0003528 upregulates CTLA4 by downregulating miR-224-5p, miR-324-5p, and miR-488-5p to promote macrophage polarization (80).…”

Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing

“…In fact, M. tuberculosis possesses different mechanisms to evade autophagy and phagosome maturation that allow these bacteria to survive intracellularly [ 56 , 57 , 58 ]. Several mycobacterial mechanisms are involved in circumventing autophagy, including lipid virulence factors such as sulfoglycolipids and phthiocerol dimycocerosates that directly inhibit autophagy [ 59 ].…”