ArticleOtology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology2020
Toll-like Receptor 4 Signaling and Downstream Neutrophilic Inflammation Mediate Endotoxemia-Enhanced Blood-Labyrinth Barrier Trafficking.
Article in Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed, 14 citations in OpenAlex.
- Early life visceral stress induces auditory brainstem sensitization and cochlear proteomic alterations in a rat model of irritable bowel syndrome.Neurobiology of stress · 2026Article
- Sound conditioning strategy promoting paracellular permeability of the blood-labyrinth-barrier benefits inner ear drug delivery.Bioengineering & translational medicine · 2024Article
- Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer.Molecular cancer therapeutics · 2023Article
- Elevated G-CSF, IL8, and HGF in patients with definite Meniere's disease may indicate the role of NET formation in triggering autoimmunity and autoinflammation.Scientific reports · 2022Article
- MEFV, IRF8, ADA, PEPD, and NBAS gene variants and elevated serum cytokines in a patient with unilateral sporadic Meniere's disease and vascular congestion over the endolymphatic sac.Journal of otology · 2022Article
- Cryptotanshinone fromChinese medicine · 2020Article
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5 authors at 1 institution in 1 country.
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Abstract
hypothesisBoth toll-like receptor 4 (TLR4) and downstream neutrophil activity are required for endotoxemia-enhanced blood-labyrinth barrier (BLB) trafficking.
backgroundAminoglycoside and cisplatin are valuable clinical therapies; however, these drugs often cause life-long hearing loss. Endotoxemia enhances the ototoxicity of aminoglycosides and cisplatin in a TLR4 dependent mechanism for which downstream proinflammatory signaling orchestrates effector immune cells including neutrophils. Neutrophil-mediated vascular injury (NMVI) can enhance molecular trafficking across endothelial barriers and may contribute to endotoxemia-enhanced drug-induced ototoxicity.
methodsLipopolysaccharide (LPS) hypo-responsive TLR4-KO mice and congenitally neutropenic granulocyte colony-stimulating factor (GCSF) GCSF-KO mice were studied to investigate the relative contributions of TLR4 signaling and downstream neutrophil activity to endotoxemia-enhanced BLB trafficking. C57Bl/6 wild-type mice were used as a positive control. Mice were treated with LPS and 24 hours later cochleae were analyzed for gene transcription of innate inflammatory cytokine/chemokine signaling molecules, neutrophil recruitment, and vascular trafficking of the paracellular tracer biocytin-TMR.
resultsCochlear transcription of innate proinflammatory cytokines/chemokines was increased in endotoxemic C57Bl/6 and GCSF-KO, but not in TLR4-KO mice. More neutrophils were recruited to endotoxemic C57Bl/6 cochleae compared with both TLR4 and GCSF-KO cochleae. Endotoxemia enhanced BLB trafficking of biocytin-TMR in endotoxemic C57Bl/6 cochleae and this was attenuated in both TLR4 and GCSF-KO mice.
conclusionTogether these results suggest that TLR4-mediated innate immunity cytokine/chemokine signaling alone is not sufficient for endotoxemia-enhanced trafficking of biocytin-TMR and that downstream neutrophil activity is required to enhance BLB trafficking. Clinically, targeting neutrophilic inflammation could protect hearing during aminoglycoside, cisplatin, or other ototoxic drug therapies.
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