Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss.
Cochlear lateral wall has recently been reported as a common site of inflammation, yet precise molecular mechanisms of the inflammatory responses remain elucidated. The present study examined the inflammatory responses in the lateral wall following acute mitochondrial dysfunction induced by a mitoch...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3948682?pdf=render |
| _version_ | 1818504164328603648 |
|---|---|
| author | Masato Fujioka Yasuhide Okamoto Seiichi Shinden Hirotaka James Okano Hideyuki Okano Kaoru Ogawa Tatsuo Matsunaga |
| author_facet | Masato Fujioka Yasuhide Okamoto Seiichi Shinden Hirotaka James Okano Hideyuki Okano Kaoru Ogawa Tatsuo Matsunaga |
| author_sort | Masato Fujioka |
| collection | DOAJ |
| description | Cochlear lateral wall has recently been reported as a common site of inflammation, yet precise molecular mechanisms of the inflammatory responses remain elucidated. The present study examined the inflammatory responses in the lateral wall following acute mitochondrial dysfunction induced by a mitochondrial toxin, 3-nitropropionic acid (3-NP). Reverse-transcription (RT)-PCR revealed increases in the expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Immunohistochemistry showed an increase in the number of activated cochlear macrophages in the lateral wall, which were in close proximity to IL-6-expressing cells. A genome-wide DNA microarray analysis of the lateral wall revealed that 35% and 60% of the genes showing >2-fold upregulation at 1 d and 3 d post-3-NP administration, respectively, were inflammatory genes, including CC- and CXC-type chemokine genes. High expression of CCL-1, 2, and 3 at 1 d, and of CCL-1, 2, 3, 4, and 5, CCR-2 and 5, and CX3CR1 at 3 d post-3-NP administration, coupled with no change in the level of CX3CL1 expression suggested that macrophages and monocytes may be involved in the inflammatory response to 3-NP-mediated injury. Quantitative (q)RT-PCR showed a transient induction of IL-1β and IL-6 expression within 24 h of 3-NP-mediated injury, followed by sustained expression of the chemoattractants, CCL-2, 4 and 5, up until 7 d after injury. The expression of CCL-2 and IL-6 was higher in animals showing permanent hearing impairment than in those showing temporary hearing impairment, suggesting that these inflammatory responses may be detrimental to hearing recovery. The present findings suggest that acute mitochondrial dysfunction induces secondary inflammatory responses in the lateral wall of the cochlear and that the IL-6/CCL-2 inflammatory pathway is involved in monocyte activation. Therefore, these secondary inflammatory responses may be a potential post-insult therapeutic target for treatments aimed at preventing the damage caused by acute mitochondrial dysfunction in the cochlear lateral wall. |
| first_indexed | 2024-12-10T21:33:32Z |
| format | Article |
| id | doaj.art-c1a666e11b33441aa70163d378be987e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T21:33:32Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c1a666e11b33441aa70163d378be987e2022-12-22T01:32:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9008910.1371/journal.pone.0090089Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss.Masato FujiokaYasuhide OkamotoSeiichi ShindenHirotaka James OkanoHideyuki OkanoKaoru OgawaTatsuo MatsunagaCochlear lateral wall has recently been reported as a common site of inflammation, yet precise molecular mechanisms of the inflammatory responses remain elucidated. The present study examined the inflammatory responses in the lateral wall following acute mitochondrial dysfunction induced by a mitochondrial toxin, 3-nitropropionic acid (3-NP). Reverse-transcription (RT)-PCR revealed increases in the expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Immunohistochemistry showed an increase in the number of activated cochlear macrophages in the lateral wall, which were in close proximity to IL-6-expressing cells. A genome-wide DNA microarray analysis of the lateral wall revealed that 35% and 60% of the genes showing >2-fold upregulation at 1 d and 3 d post-3-NP administration, respectively, were inflammatory genes, including CC- and CXC-type chemokine genes. High expression of CCL-1, 2, and 3 at 1 d, and of CCL-1, 2, 3, 4, and 5, CCR-2 and 5, and CX3CR1 at 3 d post-3-NP administration, coupled with no change in the level of CX3CL1 expression suggested that macrophages and monocytes may be involved in the inflammatory response to 3-NP-mediated injury. Quantitative (q)RT-PCR showed a transient induction of IL-1β and IL-6 expression within 24 h of 3-NP-mediated injury, followed by sustained expression of the chemoattractants, CCL-2, 4 and 5, up until 7 d after injury. The expression of CCL-2 and IL-6 was higher in animals showing permanent hearing impairment than in those showing temporary hearing impairment, suggesting that these inflammatory responses may be detrimental to hearing recovery. The present findings suggest that acute mitochondrial dysfunction induces secondary inflammatory responses in the lateral wall of the cochlear and that the IL-6/CCL-2 inflammatory pathway is involved in monocyte activation. Therefore, these secondary inflammatory responses may be a potential post-insult therapeutic target for treatments aimed at preventing the damage caused by acute mitochondrial dysfunction in the cochlear lateral wall.http://europepmc.org/articles/PMC3948682?pdf=render |
| spellingShingle | Masato Fujioka Yasuhide Okamoto Seiichi Shinden Hirotaka James Okano Hideyuki Okano Kaoru Ogawa Tatsuo Matsunaga Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss. PLoS ONE |
| title | Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss. |
| title_full | Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss. |
| title_fullStr | Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss. |
| title_full_unstemmed | Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss. |
| title_short | Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss. |
| title_sort | pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall a potential therapeutic target for sensorineural hearing loss |
| url | http://europepmc.org/articles/PMC3948682?pdf=render |
| work_keys_str_mv | AT masatofujioka pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss AT yasuhideokamoto pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss AT seiichishinden pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss AT hirotakajamesokano pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss AT hideyukiokano pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss AT kaoruogawa pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss AT tatsuomatsunaga pharmacologicalinhibitionofcochlearmitochondrialrespiratorychaininducessecondaryinflammationinthelateralwallapotentialtherapeutictargetforsensorineuralhearingloss |