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

Meniere'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 Meniere'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 Meniere's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1 beta 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 Meniere's disease pathogenesis. The immune response has been suggested to be involved in the pathology of Meniere's disease. Here the authors implicate serum glucocorticoid-inducible kinase 1 as a regulator of the NLRP3 inflammasome and link to macrophage function in a model of Meniere's disease pathology.

Automated summary

Meniere's disease is a multifactorial disorder of the inner ear characterized by severe vertigo episodes and hearing loss. This study reveals that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in Meniere's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion enhances IL-1 beta production, leading to inner ear damage.