Cytokine secretion and pyroptosis of cholesteatoma keratinocytes mediated by AIM2 inflammasomes in response to cytoplasmic DNA.

Abstract

Cholesteatoma constitutes an acquired benign epidermal non-permanent bone lesion that is locally destructive and patients often relapse. Inflammasomes, which mediate the maturation and production of IL-18 and IL-1β, resulting in pyroptosis, have been documented to serve a core function in multiple inflammatory conditions. Absent in melanoma 2 (AIM2) is an inflammasome that identifies cytoplasmic DNA and has previously been reported as a pivotal modulator of inflammatory responses. Therefore, the present study aimed to determine the expression levels of AIM2 in human cholesteatoma tissues, and elucidate its function in modulating cytokine production. The expression levels of IL-18, apoptosis-associated speck-like protein containing a CARD (ASC), IL-1β, AIM2 and caspase-1 were markedly elevated in cholesteatoma tissues. Protein expression levels of AIM2, caspase-1 and ASC were localized in the cellular cytoplasm, primarily in the granular and prickle-cell layers in the cholesteatoma epithelium. Induction using IFN-γ, as well as cytoplasmic DNA markedly activated the AIM2 inflammasome and elevated the release of IL-18 and IL-1β in human cholesteatoma keratinocytes. IFN-γ was found to enhance poly(dA:dT)-induced pyroptosis of cells and cytokine production. The results of the present study revealed that AIM2 expressed in human cholesteatoma serves a vital function in the inflammatory response by initiating the inflammasome signaling cascade in cholesteatoma.