Therapeutic Potential of 1‑(1,2,3,5,6,7-Hexahydro‑s‑indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea (MCC950), a Potent Agent for Improving Autoinflammatory Hearing Loss in Mice with Myeloid Cell-Specific Conditional Expression of Mutant Nucleotide-Binding Oligomerization Domain, Leucine-Rich Repeat, and Pyrin Domain-Containing Protein 3 (Nlrp3)

Autoinflammatory hearing loss due to NLRP3 inflammasome activation is poorly understood. We developed a novel myeloid-specific Nlrp3 mutant mouse model (Nlrp3 (D301NneoR/+); LysM (Cre/+)) expressing the D301N Nlrp3 variant in macrophages and neutrophils, offering a platform for studying inflammasome-mediated cochlear inflammation and hearing loss. Quantitative PCR and MRI showed elevated Nlrp3 expression in the cochlea, with significant inflammatory changes in cochlear and middle ear regions. Histology revealed strial vascular degeneration, contributing to hearing loss. We tested MCC950, a selective NLRP3 inflammasome inhibitor, which significantly improved auditory thresholds, especially in the 8-32 kHz range, and reduced cochlear inflammation, as shown by decreased IL-1β levels. MCC950 also improved overall health, including weight gain and reduced alopecia. Its small size and selective inhibition make it a promising alternative to existing treatments like Anakinra and Canakinumab. These findings position MCC950 as a potential treatment for NLRP3 mutation-associated hearing loss.