title: TLR4 drives the pathogenesis of acquired cholesteatoma by promoting local inflammation and bone destruction.
abstract: Acquired cholesteatoma is a chronic inflammatory disease characterized by both hyperkeratinized squamous epithelial overgrowth and bone destruction. Toll-like receptor (TLR) activation and subsequent inflammatory cytokine production are closely associated with inflammatory bone disease. However, the expression and function of TLRs in cholesteatoma remain unclear.We observed inflammatory cell infiltration of the matrix and prematrix of human acquired cholesteatoma, as well as dramatically increased expression of TLR4 and the pro-inflammatory cytokines TNF-α and IL-1β. TLR2 exhibited an up-regulation that was not statistically significant. TLR4 expression in human acquired cholesteatoma correlated with disease severity; the number of TLR4-positive cells increased with an increased degree of cholesteatoma, invasion, bone destruction, and hearing loss. Moreover, TLR4 deficiency was protective against experimental acquired cholesteatoma-driven bone destruction and hearing loss, as it reduced local TNF-α and IL-1β expression and impaired osteoclast formation by decreasing expression of the osteoclast effectors receptor activator of nuclear factor (NF)-κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP). TLR2 deficiency did not relieve disease severity, inflammatory responses, or osteoclast formation. Moreover, neither TLR2 nor TLR4 deficiency had an effect on antimicrobial peptides, inducible iNOS,BD-2 expression or bacterial clearance. Therefore, TLR4 may promote cholesteatoma-induced bone destruction and deafness by enhancing inflammatory responses and osteoclastogenesis.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Si
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, The third affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630. China.
authors.forename: Yu Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Sui Jun
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Yi Qing
authors.initials: YQ
authors.lastname: Zheng
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Huai Li
authors.initials: HL
authors.lastname: Jiang
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Guo
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Zhuo Hao
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Qiu Hong
authors.initials: QH
authors.lastname: Huang
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120. China.|Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, 510120. China.
authors.forename: Zhi Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology*; D002452:Cell Count; D002781:Cholesteatoma / Q000151:congenital / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D003710:Demography; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D034381:Hearing Loss / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051197:Toll-Like Receptor 4