期刊
MOLECULAR IMMUNOLOGY
卷 149, 期 -, 页码 66-76出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2022.06.006
关键词
Kanamycin; NLRP3; Pyroptosis; Hearing loss; Oridonin
资金
- National Natural Science Foundation of China [81800916, 82071037, 81770997]
- Natu-ral Science Foundation of the Jiangsu Higher Education Institutions of China [18KJA320011, 19KJA560002]
- Nature Science Foundation of Xuzhou [KC20177]
- Special Fund for Clinical Scientific Research of Jieping Wu Foundation [320.6750.18327]
- Science and Tech-nology Project of Shenzhen [JCYJ20180305163801016, JCYJ20210324114204012]
This study demonstrates the involvement of NLRP3 inflammasomes in aminoglycoside-induced hearing loss. Activation of NLRP3 inflammasomes may lead to hair cell death and inflammatory response, resulting in hearing loss. Inhibiting the activation of NLRP3 inflammasomes can rescue aminoglycoside-related hearing loss.
Aminoglycoside antibiotic drugs induce hearing loss in children and adults every year; however, the pathological mechanisms remain unknown. Previous studies have shown that the accumulation of reactive oxygen species (ROS) and inflammation in the inner ear may be responsible for kanamycin (KM)-induced hair cell death and hearing loss. Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) is a specific ROS sensor that initiates inflammasome assembly as well as activates caspase-1 and downstream inflammatory factors. Therefore, this study aimed to determine whether NLRP3 inflamma-somes are involved in KM-related hearing loss in mice. Compared with the control (saline) group, increased levels of activated caspase-1, interleukin (IL)-1 beta, IL-18, N-terminal fragment of gasdermin D (GSDMD-N), and NLRP3 were detected by immunofluorescence, western blot, and enzyme-linked immunosorbent assay (ELISA) in the KM-plus-furosemide (LASIX)-treated group. Moreover, we also found that the NLRP3 inhibitor oridonin (Ori) could significantly rescue KM-related hearing loss by inhibiting NLRP3-inflammasome activation and caspase-1/ GSDMD-related hair cell pyroptosis. These findings demonstrate that apoptosis, as well as pyroptosis, may be involved in KM-related hearing loss and that the NLRP3/caspase-1/GSDMD pathway may be a new target for treating aminoglycoside-induced hearing loss.
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