%0 Journal Article
%T Therapeutic effect of NLRP3 inhibition on hearing loss induced by systemic inflammation in a CAPS-associated mouse model.
%A Ma JH
%A Lee E
%A Yoon SH
%A Min H
%A Oh JH
%A Hwang I
%A Sung Y
%A Ryu JH
%A Bok J
%A Yu JW
%A Ma JH
%A Lee E
%A Yoon SH
%A Min H
%A Oh JH
%A Hwang I
%A Sung Y
%A Ryu JH
%A Bok J
%A Yu JW
%A Ma JH
%A Lee E
%A Yoon SH
%A Min H
%A Oh JH
%A Hwang I
%A Sung Y
%A Ryu JH
%A Bok J
%A Yu JW
%J EBioMedicine
%V 82
%N 0
%D Aug 2022
%M 35870427
%F 11.205
%R 10.1016/j.ebiom.2022.104184
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.<BR><B>BACKGROUND: </B>National Research Foundation of Korea Grant funded by the Korean Government and the Team Science Award of Yonsei University College of Medicine.