한빛사논문
- 조회684
Ji-Hyun Ma,a,1 Eunju Lee,b,1 Sung-Hyun Yoon,b,1 Hyehyun Min,a,1 Jae Hwan Oh,a Inhwa Hwang,b Yejin Sung,c Ju Hee Ryu,c Jinwoong Bok,a* and Je-Wook Yub*
aDepartment of Anatomy, Brain Korea 21 Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
bDepartment of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
cTheragnosis Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
*Corresponding author
1These authors equally contributed to this paper.
Abstract
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.
논문정보
- Research article
- 2022년 08월 (BRIC 등록일 2022-08-22)
- 국내 연구진
- 생명과학 > 면역학
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