METHODS: We generated a mice with conditional expression of CAPS-associated NLRP3 mutant (D301N) in cochlea-resident CX3CR1 macrophages and examined the susceptibility of CAPS mice to inflammation-mediated hearing loss in a local and systemic inflammation context.
RESULTS: Upon lipopolysaccharide (LPS) injection into middle ear cavity, NLRP3 mutant mice exhibited severe cochlear inflammation, inflammasome activation and hearing loss. However, this middle ear injection model induced a considerable hearing loss in control mice and inevitably caused an inflammation-independent hearing loss possibly due to ear tissue damages by injection procedure. Subsequently, we optimized a systemic LPS injection model, which induced a significant hearing loss in NLRP3 mutant mice but not in control mice. Peripheral inflammation induced by a repetitive low dose of LPS injection caused a blood-labyrinth barrier disruption, macrophage infiltration into cochlea and cochlear inflammasome activation in an NLRP3-dependent manner. Interestingly, both cochlea-infiltrating and -resident macrophages contribute to peripheral inflammation-mediated hearing loss of CAPS mice. Furthermore, NLRP3-specific inhibitor, MCC950, as well as an interleukin-1 receptor antagonist significantly alleviated systemic LPS-induced hearing loss and inflammatory phenotypes in NLRP3 mutant mice.
CONCLUSIONS: Our findings reveal that CAPS-associated NLRP3 mutation is critical for peripheral inflammation-induced hearing loss in our CAPS mice model, and an NLRP3-specific inhibitor can be used to treat inflammation-mediated sensorineural hearing loss.
BACKGROUND: National Research Foundation of Korea Grant funded by the Korean Government and the Team Science Award of Yonsei University College of Medicine.
方法:我们产生了小鼠,在耳蜗驻留的CX3CR1巨噬细胞中条件表达了CAPS相关的NLRP3突变体(D301N),并检查了CAPS小鼠在局部和全身炎症环境中对炎症介导的听力损失的易感性。
结果:中耳腔注射脂多糖(LPS)后,NLRP3突变小鼠表现出严重的耳蜗炎症,炎症体激活和听力损失。然而,这种中耳注射模型在对照小鼠中引起相当大的听力损失,并且不可避免地引起不依赖炎症的听力损失,这可能是由于注射程序引起的耳组织损伤。随后,我们优化了全身LPS注射模型,在NLRP3突变小鼠中引起明显的听力损失,但在对照小鼠中没有。反复低剂量注射LPS引起的外周炎症导致血液迷宫屏障破坏,巨噬细胞以NLRP3依赖性方式渗入耳蜗和耳蜗炎症体激活。有趣的是,耳蜗浸润巨噬细胞和常驻巨噬细胞均导致CAPS小鼠外周炎症介导的听力损失.此外,NLRP3特异性抑制剂,MCC950和白介素-1受体拮抗剂可显着减轻NLRP3突变小鼠的全身性LPS诱导的听力损失和炎症表型。
结论:我们的研究结果表明,在我们的CAPS小鼠模型中,CAPS相关的NLRP3突变对于外周炎症诱导的听力损失至关重要,NLRP3特异性抑制剂可用于治疗炎症介导的感觉神经性听力损失。
背景:韩国国家研究基金会由韩国政府和延世大学医学院团队科学奖资助。