Silencing Nrf2 attenuates chronic suppurative otitis media by inhibiting pro-inflammatory cytokine secretion through up-regulating TLR4

Abstract

Compromised TLR-mediated chronic inflammation contributes to bacterial infection-caused chronic suppurative otitis media, but the mechanisms are unclear. The present study examined the expression status of nuclear erythroid 2-related factor 2 (Nrf2) and TLRs in human middle-ear mucosae tissues collected from patients with chronic suppurative otitis media, chronic otitis media and non-otitis media, and found that Nrf2 was high-expressed, whereas TLR4, instead of other TLRs, was low expressed in chronic suppurative otitis media compared to chronic otitis media and non-chronic otitis media groups. Consistently, inflammatory cytokines were significantly up-regulated in the chronic suppurative otitis media group, instead of the chronic otitis media and non-chronic otitis media groups. Next, LPS-induced acute otitis media and chronic suppurative otitis media models in mice were established, and high levels of inflammatory cytokines were sustained in the mucosae tissues of chronic suppurative otitis media mice compared to the non-otitis media and acute otitis media groups. Interestingly, continuous low-dose LPS stimulation promoted Nrf2 expression, but decreased TLR4 levels in chronic suppurative otitis media mice mucosae. In addition, knock-down of Nrf2 increased TLR4 expression levels in chronic suppurative otitis media mice, and both Nrf2 ablation and TLR4 overexpression inhibited the pro-inflammatory cytokine expression in chronic suppurative otitis media. Finally, we found that both Nrf2 overexpression and TLR4 deficiency promoted chronic inflammation in LPS-induced acute otitis media mice models. Taken together, knock-down of Nrf2 reversed chronic inflammation to attenuate chronic suppurative otitis media by up-regulating TLR4.

Toll-Like Receptors: Expression and Roles in Otitis Media

“…A comparison of the middle ear mucosa of non-otitis media, COM, and CSOM groups showed that mRNA and protein levels of TLR4 were not different between non-otitis media and COM groups, but were significantly decreased in the CSOM group. These authors thus concluded that reduced TLR4 levels in the middle ear mucosa cause a persistent inflammatory response and weaken susceptibility to CSOM [30,40].…”

LR4 gene expression in patients with chronic suppurative otitis media

“…The Tlr4 gene expression levels were not altered in children with a history of OM compared to control in middle ear tissue samples [15]. Also, the Tlr4 gene expression is downregulated in middle ear tissue samples of CSOM patients in comparison to controls [16]. Together these report suggest that Tlr4 gene expression were downregulated in OM.…”

“…In our present study we aim to compare the expression of the TLR4 gene in the blood samples of CSOM patients and healthy controls. A case-control study was carried out by involving 16 participants in each group. The levels of the TLR4 gene expression were measured by using the qRT-PCR method.…”

Long non‑coding RNA NEAT1 contributes to lipopolysaccharide‑induced inflammation and apoptosis of human middle ear epithelial cells via regulating the miR‑301b‑3p/TLR4 axis

“…Therefore, the present study aimed to investigate the NEAT1/miR-301b-3p/TLR4 regulatory network, in the hope of revealing a new theoretical basis for the application of NEAT1 in the treatment of AOM. In the present study, LPS was used to establish the cell model of AOM and investigate the potential mechanism (26,32). According to previous reports, NEAT1 is induced in multiple immune system diseases, such as pneumonia (15), hepatitis (17) and osteoarthritis (33).…”