TLR-4/microRNA-125a/NF-κB signaling modulates the immune response to Mycobacterium tuberculosis infection

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, could lead to kinds of clinical disorders and remains a leading global health problem, resulting in great morbidity and mortality worldwide. Previous studies have firmly demonstrated that M. tuberculosis (M.tb) has evolved to utilize different mechanisms to evade or attenuate the host immune response, such as regulation of immune-related genes by modulation of miRNAs of host or bacteria. However, the knowledge of functions of miRNAs during M.tb infection remains limited. Here, we reported that a host microRNA, miR-125a, was significantly up-regulated by M.tb infection in both RAW264.7 and THP-1cells, in a TLR4 signaling-dependent manner. Subsequently, our results demonstrated that miR-125a was a negative regulator of NF-kB pathway by directly targeting TRAF6, resulting in the suppression of cytokines, attenuation of immune response and promotion of M.tb survival. Taken together, our findings provide a novel detailed molecular mechanism in which miR-125a was enhanced to inhibit inflammatory cytokines secretion and attenuate the immune response during M.tb infection in RAW264.7 and THP-1 cells, and suggest an intrinsic a promising anti-M.tb therapeutic target.

Elevated circulating lnc‐ANRIL/miR‐125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis

“…28 An experiment reveals that miR-125a negative regulates NF-kB pathway via directly targeting TRAF6, reducing the inflammatory cytokines expressions in mycobacterium tuberculosis infection. 19 It is also reported that miR-125a mimic ameliorates the effect of IL-6 on promoting the neutrophil chemoattractant expression both in vitro and in vivo in lung inflammation. 17 Another experiment reports that miR-125a targets effector programs and subsequently stabilizes the immune homeostasis mediated by Tregs.…”

“…miR‐125a belongs to the miR‐125 family, and the family includes miR‐125a, miR‐125b1 and miR‐126b2 . An experiment reveals that miR‐125a negative regulates NF‐kB pathway via directly targeting TRAF6, reducing the inflammatory cytokines expressions in mycobacterium tuberculosis infection . It is also reported that miR‐125a mimic ameliorates the effect of IL‐6 on promoting the neutrophil chemoattractant expression both in vitro and in vivo in lung inflammation .…”

“…miR‐125a, a highly reserved miRNA locating on chromosome 19, 11, and 21, is also closely related to inflammation and immunity, and this miRNA has been reported to have the potential in regulating sepsis pathogenesis . Moreover, it is a direct target of lnc‐ANRIL, and the lnc‐ANRIL/miR‐125a axis has been indicated in many diseases . However, the role of lnc‐ANRIL/miR‐125a axis in sepsis remains unknown.…”

“…15,16 Moreover, it is a direct target of lnc-ANRIL, and the lnc-ANRIL/miR-125a axis has been indicated in many diseases. [17][18][19][20][21] However, the role of lnc-ANRIL/miR-125a axis in sepsis remains unknown.…”

MiR‐140 modulates the inflammatory responses of Mycobacterium tuberculosis‐infected macrophages by targeting TRAF6

“…There are many potential targets were predicted, and TRAF6 was selected from these predicted targets for further validation, as TRAF6 has been reported for its role in M tb infection. 20 The bioinformatics analysis showed that TRAF6 was one of the miR-140targeted genes, and the complementary sequences between miR-140 and TRAF6 3′UTR were shown in Figure 5A…”