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.

TLR 介导的慢性炎症受损会导致细菌感染引起的慢性化脓性中耳炎，但其机制尚不清楚。本研究检测了慢性化脓性中耳炎、慢性中耳炎和非中耳炎患者中耳粘膜组织中核红细胞2相关因子2（Nrf2）和TLRs的表达状况，发现Nrf2与慢性中耳炎组和非慢性中耳炎组相比，TLR4 在慢性化脓性中耳炎中低表达，而非其他 TLRs。一致地，慢性化脓性中耳炎组的炎症细胞因子显着上调，而不是慢性中耳炎和非慢性中耳炎组。接下来，建立了LPS诱导的小鼠急性中耳炎和慢性化脓性中耳炎模型，与非中耳炎组和急性中耳炎组相比，慢性化脓性中耳炎小鼠的粘膜组织中持续存在高水平的炎症细胞因子。有趣的是，持续的低剂量LPS​​刺激促进了慢性化脓性中耳炎小鼠粘膜中Nrf2的表达，但降低了TLR4的水平。此外，敲低Nrf2会增加慢性化脓性中耳炎小鼠中TLR4的表达水平，并且Nrf2敲除和TLR4过表达都会抑制慢性化脓性中耳炎中促炎细胞因子的表达。最后，我们发现 Nrf2 过表达和 TLR4 缺乏都会促进 LPS 诱导的急性中耳炎小鼠模型的慢性炎症。总而言之，敲除 Nrf2 可逆转慢性炎症，通过上调 TLR4 来减轻慢性化脓性中耳炎。