NOD-Like Receptor Signaling in Cholesteatoma.
Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results. The expression of NOD2 mRNA and protein was significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2, or TLR4 in cholesteatoma. Moreover, regulation of genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, and PYCARD, the downstream molecules IRAK1 and antiapoptotic regulator CFLAR showed significant upregulation, whereas SMAD3, a proapoptotic inducer, was significantly downregulated. Finally, altered regulation of inflammatory target genes of NOD signaling was detected. Conclusions. These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules is involved in the etiopathogenesis and growth of cholesteatoma.
Department of Otorhinolaryngology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Anke
A
Leichtle
Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Teutoburger Straße 50, 33604 Bielefeld, Germany.
Christin
C
Klenke
Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Teutoburger Straße 50, 33604 Bielefeld, Germany.
Joerg
J
Ebmeyer
Department of Otorhinolaryngology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Markus
M
Daerr
Department of Otorhinolaryngology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Karl-Ludwig
KL
Bruchhage
Department of Otorhinolaryngology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Anna Sophie
AS
Hoffmann
Division of Otolaryngology, Department of Surgery, University of California, San Diego and VA Medical Center, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Allen F
AF
Ryan
Department of Otorhinolaryngology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Barbara
B
Wollenberg
Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Teutoburger Straße 50, 33604 Bielefeld, Germany.
Holger
H
Sudhoff
D053468:CARD Signaling Adaptor Proteins / Q000096:biosynthesis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D002781:Cholesteatoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D046228:Microarray Analysis; D053473:Nod2 Signaling Adaptor Protein / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; C435692:NLRC4 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C402202:PYCARD protein, human; D012333:RNA, Messenger; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2