The Upregulation of IL-1β Induced by Cisplatin Triggers PI3K/AKT/MMP9 Pathway in Pericytes Mediating the Leakage of the Blood Labyrinth Barrier

Background: Blood-labyrinth barrier (BLB) damage has been recognized as a key mechanism underlying cisplatin (CDDP)-induced hearing loss. Inflammation within the cochlea, triggered by CDDP, is a key pathological response. However, the relationship between CDDP-induced inflammation and BLB dysfunction remains elusive.

Materials and methods: In vivo and in vitro BLB models were used to explore the inflammatory mechanisms underlying CDDP ototoxicity. C57BL/6J mice were treated with CDDP and IL-1β levels, BLB permeability, and hearing thresholds were assessed using ELISA, histological staining, ABR test and BLB leakage tests. In vitro BLB models, the effect of IL-1β on MMP9 expression, PI3K-AKT pathway activation, and endothelial barrier permeability were examined via Western blot, TEER value test, and FITC extraction analysis. In addition, inhibitors of IL-1β, MMP9, and PI3K-AKT were used to analyze the specific mechanisms.

Results: After CDDP treatment, IL-1β upregulation in the stria vascularis disrupted tight junctions, increased BLB permeability, and led to hearing loss. Notably, IL-1β inhibition with AS101 attenuated hearing threshold elevation and BLB damage in CDDP-treated mice. Mechanistically, CDDP triggered IL-1β release from endothelial cells. IL-1β promoted MMP9 secretion from pericytes via the PI3K/Akt pathway, leading to disruption of tight junctions. Both MMP9 and PI3K-AKT inhibitors abrogated IL-1β-induced changes.

Conclusion: Our findings suggest that CDDP initiates a cascade of events starting with IL-1β release from endothelial cells. This release triggers the activation of PI3K/Akt pathway and upregulation of MMP9 expression in pericytes, which increases BLB permeability and leds to hearing loss. IL-1β and the PI3K-AKT pathway are promising therapeutic targets,offering hope for patients with CDDP-induced hearing loss.

BLB; IL-1β; MMP9; PI3K/AKT pathway; cisplatin.