miR-582-5p Is Upregulated in Patients with Active Tuberculosis and Inhibits Apoptosis of Monocytes by Targeting FOXO1

Abstract

Macrophage apoptosis is a host innate defense mechanism against tuberculosis (TB). In this study, we found that percentage of apoptotic cells in peripheral blood monocytes from patients with active TB was lower than that from healthy controls (p<0.001). To understand whether microRNAs can modulate apoptosis of monocytes, we investigated differentially expressed microRNAs in patients with active TB. miR-582-5p was mainly expressed in monocytes and was upregulated in patients with active TB. The apoptotic percentage of THP-1 cells transfected with miR-582-5p mimics was significantly lower than those transfected with negative control of microRNA mimics (p<0.001), suggesting that miR-582-5p could inhibit apoptosis of monocytes. To our knowledge, the role of miR-582-5p in regulating apoptosis of monocytes has not been reported so far. Systematic bioinformatics analysis indicated that FOXO1 might be a target gene for miR-582-5p and its 3′UTR contains potential binding sites for miR-582-5p. To determine whether miR-582-5p could influence FOXO1 expression, miR-582-5p mimics or negative control of microRNA mimics were transfected into THP-1 cells. RT-PCR and western blot analysis showed that the miR-582-5p could suppress both FOXO1 mRNA and protein expression. Co-transfection of miR-582-5p and FOXO1 3′UTR-luciferase reporter vector into cells demonstrated that significant decrease in luciferase activity was only found in reporter vector that contained a wild type sequence of FOXO1 3′UTR, suggesting that miR-582-5p could directly target FOXO1. In conclusion, miR-582-5p inhibited apoptosis of monocytes by down-regulating FOXO1 expression and might play an important role in regulating anti-M. tuberculosis directed immune responses.

Biomarkers for risk of developing active tuberculosis in contacts of TB patients: a prospective cohort study

“…The high count of peripheral monocytes also observed in the TB contacts prior to progression to an active TB in the present study is consistent with the hypothesis that this could be a biomarker for progressive TB [42,43], and our study suggests that this is the case even before the appearance of symptoms.…”

“…It has already been reported that patients with active TB have an increased frequency of peripheral blood monocytes compared to healthy individuals, and this study and others have shown that effective anti-TB chemotherapy can reverse this [17,41,42]. The high count of peripheral monocytes also observed in the TB contacts prior to progression to an active TB in the present study is consistent with the hypothesis that this could be a biomarker for progressive TB [42,43], and our study suggests that this is the case even before the appearance of symptoms.…”

Mycobacterium tuberculosisDecreases Human Macrophage IFN-γ Responsiveness through miR-132 and miR-26a

“…However, with some exceptions (17,(30)(31)(32)(33)(34)(35), the majority of these studies have failed to identify downstream effects on the host immune response for the miRNAs detected with altered expression. A major contributing factor to the lack of concrete targets is the use of mixed cell populations or sputum for the identification of differentially expressed miRNAs during M. tuberculosis infection.…”

Diagnostic values of microRNA-31 in peripheral blood mononuclear cells for pediatric pulmonary tuberculosis in Chinese patients

“…In addition, Wu et al found that miR-155 and miR-155* are potential diagnostic markers that are up-regulated during immune challenge with MtB antigens (Wu et al, 2012). Liu et al also demonstrated that miR-582-5p plays an essential role in regulating anti-MtB directed immune responses by inhibiting monocyte apoptosis as well as down-regulating FOXO1 expression (Liu et al, 2013).…”