Abstract
BackgroundOtitis media (OM), one of the most common pediatric infectious diseases, causes inner ear inflammation resulting in vertigo and sensorineural hearing loss. Previously, we showed that spiral ligament fibrocytes (SLFs) recognize OM pathogens and up-regulate chemokines. Here, we aim to determine a key molecule derived from SLFs, contributing to OM-induced inner ear inflammation.MethodsLive NTHI was injected into the murine middle ear through the tympanic membrane, and histological analysis was performed after harvesting the temporal bones. Migration assays were conducted using the conditioned medium of NTHI-exposed SLFs with and without inhibition of MCP-1/CCL2 and CCR2. qRT-PCR analysis was performed to demonstrate a compensatory up-regulation of alternative genes induced by the targeting of MCP-1/CCL2 or CCR2.ResultsTranstympanic inoculation of live NTHI developed serous and purulent labyrinthitis after clearance of OM. THP-1 cells actively migrated and invaded the extracellular matrix in response to the conditioned medium of NTHI-exposed SLFs. This migratory activity was markedly inhibited by the viral CC chemokine inhibitor and the deficiency of MCP-1/CCL2, indicating that MCP-1/CCL2 is a main attractant of THP-1 cells among the SLF-derived molecules. We further demonstrated that CCR2 deficiency inhibits migration of monocyte-like cells in response to NTHI-induced SLF-derived molecules. Immunolabeling showed an increase in MCP-1/CCL2 expression in the cochlear lateral wall of the NTHI-inoculated group. Contrary to the in vitro data, deficiency of MCP-1/CCL2 or CCR2 did not inhibit OM-induced inner ear inflammation in vivo. We demonstrated that targeting MCP-1/CCL2 enhances NTHI-induced up-regulation of MCP-2/CCL8 in SLFs and up-regulates the basal expression of CCR2 in the splenocytes. We also found that targeting CCR2 enhances NTHI-induced up-regulation of MCP-1/CCL2 in SLFs.ConclusionsTaken together, we suggest that NTHI-induced SLF-derived MCP-1/CCL2 is a key molecule contributing to inner ear inflammation through CCR2-mediated recruitment of monocytes. However, deficiency of MCP-1/CCL2 or CCR2 alone was limited to inhibit OM-induced inner ear inflammation due to compensation of alternative genes.
Highlights
Otitis media (OM), one of the most common pediatric infectious diseases, causes inner ear inflammation resulting in vertigo and sensorineural hearing loss
Inoculation of nontypeable H. influenzae (NTHI) into the middle ear leads to labyrinthitis It is known that middle ear inflammation leads to inner ear inflammation resulting in inner ear dysfunction [24]
It was noted that labyrinthitis remains after clearance of middle ear inflammation, indicating inner ear inflammation occurs as a complication of OM
Summary
Otitis media (OM), one of the most common pediatric infectious diseases, causes inner ear inflammation resulting in vertigo and sensorineural hearing loss. OM is not a life-threatening disease, but causes inner ear complications such as sensorineural hearing loss (SNHL) [3] and vertigo [4]. OM-induced inner ear complications of children are clinically important since even a mild hearing loss can interfere with a child’s language development, [5] and balance dysfunction is associated with delays in achievement of motor milestones [6]. OM-induced SNHL is believed to be caused by immune-mediated damage due to inner ear inflammation, which is initiated by the entry of bacterial molecules of OM pathogens into the inner ear through the round window membrane [9]. Animal studies of pneumococcal OM demonstrate cochlear damage such as hair cell loss [10] and pathologic changes in the cochlear lateral wall [11,12]
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