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.

Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS

“…Importantly, TLR4-deficiency in mice was already shown to be protective against cholesteatoma-driven hearing loss and bone destruction by reduction of local expression of pro-inflammatory cytokines and osteoclast formation [14]. In summary, we demonstrated that stem cells residing in cholesteatoma are the cellular mediators of its highly pro-inflammatory environment, suggesting a distinct role of ME-CSCs as drivers in cholesteatoma progression.…”

“…In 2015, Si and colleagues extended these findings by demonstrating TLR4 as a major driver of cholesteatoma pathogenesis in terms of promoting both inflammation and bone destruction. Expression of TLR4 was particularly shown to be correlated with disease severity in terms of increased invasion, bone destruction, and hearing loss [14]. Although an up-regulation of TLR2 was observable in cholesteatoma tissue [13], deficiency in TLR2 in mice did not affect disease severity or inflammatory responses [14].…”

“…Expression of TLR4 was particularly shown to be correlated with disease severity in terms of increased invasion, bone destruction, and hearing loss [14]. Although an up-regulation of TLR2 was observable in cholesteatoma tissue [13], deficiency in TLR2 in mice did not affect disease severity or inflammatory responses [14]. Interestingly, we observed an upregulation of TLR4 gene expression in ME-CSCs compared to ACSCs in the present study, whereas expression of TLR2 and TLR2-dependent inflammatory signaling remained unaffected in ME-CSCs.…”

Is There A Systemıc Inflammatory Effect of Cholesteatoma?

“…In the perimatrix of acquired cholesteatoma, there is inflammatory cell infiltration such as lymphocyte and polymorphonuclear cells. [12][13][14] Acute inflammation is triggered by events such as bacterial or viral infections, trauma, tissue necrosis, and immune reactions. T lymphocytes play a greater role in the response of the body to viral infections.…”

Extensive qPCR analysis reveals altered gene expression in middle ear mucosa from cholesteatoma patients

“…There is not seldom a concomitant infection of the medial part of the ear canal, which leads to a faster expansion of the disease, and the only treatment is surgery [4]. Interesting findings by Si et al [19] and Jiang et al [26] show a relationship between high expression of TLR4 in cholesteatoma matrix, and local bone destruction and inflammatory response.…”