Role of ESAT-6 in renal injury by regulating microRNA-155 expression via TLR4/MyD88 signaling pathway in mice with Mycobacterium tuberculosis infection

Abstract

The study aims to investigate the underlying mechanism involved in the early secretory antigenic target-6 (ESAT-6) in renal injury through regulation of the expression of miR-155 through the oll-like receptor (TLR)-4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway in Mycobacterium tuberculosis (MTB)-infected mice. Sixty C57BL/6 mice with MTB-induced renal injury were randomly assigned into control, MTB, mimic, inhibitor, inhibitor + ESAT6, and inhibitor + ESAT6 + TAK242 groups. Body weight, the ratio of kidney weight to body weight (Kw/Bw), blood urea nitrogen (BUN), and serum creatinine (Scr) of mice were measured. Flow cytometry was used to detect renal activation in mice. Expressions of miR-155 and ESAT6 were detected by quantitative real-time PCR (qRT-PCR), and Western blotting was used to examine the expressions of ESAT6, TLR4, and MyD88. Expressions of tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), and interferon-γ (IFN-γ) were measured by qRT-PCR and ELISA. Compared with the control group, the BUN and Scr levels as well as the expression levels of miR-155, TLR4, MyD88, TNF-α, IL-17, and IFN-γ increased, while Kw/Bw decreased in the MTB and mimic groups. In comparison with the MTB group, the above indexes except Kw/Bw were elevated in the mimic group, but were reduced in the inhibitor group, while the Kw/Bw dropped in the mimic group but increased in the inhibitor group. Compared with the inhibitor group, the Kw/Bw decreased while the rest of the indexes increased in the inhibitor + ESAT6 group. ESAT6 may induce renal injury by promoting miR-155 expression through the TLR-4/MyD88 signaling pathway in MTB-infected mice.

Unraveling the Role of MicroRNAs in Mycobacterium tuberculosis Infection and Disease: Advances and Pitfalls

“…Also, miR-155 increased mRNA expression of TLR4, MyD88, TNF-␣, IL-17, and IFN-␥ through the TLR4 signaling pathway, promoting the progression of infection, leading to renal injuries in extra PTB disease in mice (Fig. 3I) (104).…”

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…Studies assessing Mtb proteins and kidney injury found the Mtb antigen, ESAT-6, contributed to renal injury in mice injected with a high dose of ESAT-6 by upregulating the expression of pro-inflammatory microRNA-155 via the MyD88 innate cell pathway (275,277,278). While the dose of ESAT-6 used in these studies may not reflect those found in physiological disease, this evidence may show a cyclical worsening of disease in CKD/TB coinfection exacerbated by kidney inflammation caused by TB and CKD independently.…”

Mycobacterium tuberculosisESAT6 Drives the Activation and Maturation of Bone Marrow-Derived Dendritic Cells via TLR4-Mediated Signaling

“…Murine BMDCs can produce TNF-α and IL-1β in response to ESAT6 (21). In addition, TLR4 is essential for ESAT6-induced IFN-β expression in macrophages (22), and TLR4 expression is upregulated in the renal tissues of mice with M. tuberculosis - or ESAT6-induced renal injury (25). It was also reported that TLR2 is important for ESAT6-mediated immune regulation (18).…”