Ma, Ji-Hyun Lee, Eunju Yoon, Sung-Hyun Min, Hyehyun Oh, Jae Hwan Hwang, Inhwa Sung, Yejin Ryu, Ju Hee Bok, Jinwoong Yu, Je-Wook 2024-01-19T11:32:02Z 2024-01-19T11:32:02Z 2022-08-11 2022-08 https://pubs.kist.re.kr/handle/201004/114816 Background Cryopyrin-associated periodic syndrome (CAPS) is an inherited autoinflammatory disease caused by a gain-of-function mutation in NLRP3. Although CAPS patients frequently suffer from sensorineural hearing loss, it remains unclear whether CAPS-associated mutation in NLRP3 is associated with the progression of hearing loss. 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. Findings 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. Interpretation 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. Copyright (C) 2022 The Authors. Published by Elsevier B.V. English Elsevier BV Therapeutic effect of NLRP3 inhibition on hearing loss induced by systemic inflammation in a CAPS-associated mouse model Article 10.1016/j.ebiom.2022.104184 1 EBioMedicine, v.82 EBioMedicine 82 Y scie scopus 000834135200003 Medicine, General & Internal Medicine, Research & Experimental General & Internal Medicine Research & Experimental Medicine Article CIAS1 MUTATIONS ACTIVATION INFLAMMASOMES MACROPHAGES CAPS NLRP3 inflammasome Hearing loss Cochlear inflammation Blood-labyrinth barrier disruption NLRP3 inhibitor