Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model

Dao-Gong Zhang, Wen-Qian Yu, Jia-Hui Liu, Li-Gang Kong, Na Zhang, Yong-Dong Song, Xiao-Fei Li, Zhao-Min Fan, Ya-Feng Lyu, Na Li () and Hai-Bo Wang ()
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Dao-Gong Zhang: Shandong Provincial ENT Hospital, Shandong University
Wen-Qian Yu: Shandong Provincial ENT Hospital, Shandong University
Jia-Hui Liu: Shandong Provincial ENT Hospital, Shandong University
Li-Gang Kong: Shandong Provincial ENT Hospital, Shandong University
Na Zhang: Shandong Provincial ENT Hospital, Shandong University
Yong-Dong Song: Shandong Provincial ENT Hospital, Shandong University
Xiao-Fei Li: Shandong Provincial ENT Hospital, Shandong University
Zhao-Min Fan: Shandong Provincial ENT Hospital, Shandong University
Ya-Feng Lyu: Shandong Provincial ENT Hospital, Shandong University
Na Li: Shandong Provincial ENT Hospital, Shandong University
Hai-Bo Wang: Shandong Provincial ENT Hospital, Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Ménière’s disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière’s disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière’s disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1β production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk−/− mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière’s disease pathogenesis.

Date: 2023
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DOI: 10.1038/s41467-023-36949-4

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