Learning Objectives: Innate Immunity, Cholesteatoma, Network Analysis, Regulatory Network.
Introduction: The etiopathogenesis of Cholesteatoma is controversial, but it is associated with recurrent, persistent ear infections and bacteria. Thereby the interaction between pathogen susceptibility and innate immunity is relevant. Toll-like (TLRs) and Nod-like receptors (Nods) are known to be important participants in the innate immune response to pathogens at other sites, via elaboration of inflammatory cytokines. We explored the network of Innate Immune Receptor-signalling and cytokine production in cholesteatoma.
Methods: Cholesteatoma and control tissue of the external auditory canal skin (EAS) from patients undergoing surgery were evaluated for innate immune pattern and molecules. Cholesteatoma thickness and cellular infiltration were evaluated histologically. mRNA expression of receptors and downstream molecules were evaluated by microarray, real-time PCR, while protein levels were determined by Immunhistochemistry and bioinformatical network analysis.
Results: A subset of receptors involved and downstream molecules in Innate Immunity such as TLRs, Nods and TNF are expressed in cholesteatoma. NOD2 mRNA and protein, but not TLRs or Nod-receptors were significantly induced compared to control samples of the external auditory canal skin (EAS). Moreover, regulation of genes in an interaction network of the RIPK2 was detected. In addition to NOD2, NLRC4, PYCARD, the downstream molecules IRAK1 and anti-apoptotic regulator CFLAR, showed significant upregulation, whereas SMAD3, a pro-apoptotic inducer, was significantly downregulated.
Conclusions: The network interaction of innate immune regulation is important in the etiopathogenesis and growth of cholesteatoma.