Glucocorticoid-stimulated, transcription-independent release of annexin A1 by cochlear Hensen cells.
OBJECTIVE
The current clinical strategy to protect the auditory organ against inflammatory damage by migrating leukocytes is the local delivery of glucocorticoids. However, the mechanism by which glucocorticoids confer this protection remains unknown. Therefore, we investigated the cellular and molecular targets of glucocorticoids in the cochlea that could be involved in preventing leukocyte migration.


METHODS
We used microscopy as well as immunocytochemical and microfluidic techniques to elucidate the effect of dexamethasone, hydrocortisone and prednisolone on the cellular and intracellular distribution of annexin A1 (ANXA1) - a glucocorticoid target known to inhibit leukocyte migration by receptor-mediated signalling - in the cochlea and isolated cochlear cells of guinea pigs.


RESULTS
All the cells lining the scala media - the cochlear compartment containing the auditory organ - express ANXA1 and the ANXA1 receptor FPR2/ALX is present in the scala media, as well as in other cochlear ducts. The majority of ANXA1 in the scala media is stored inside lipid droplets within cochlear Hensen cells. Glucocorticoids activate a myosin IIC-mediated mechanism that drives ANXA1 from the lipid droplets to the apical region of the Hensen cells, where ANXA1 is released to the external milieu by a process involving ABC transporters.


CONCLUSIONS
These findings suggest that ANXA1 could be a major mediator of the anti-inflammatory effects of glucocorticoids in the cochlea and identify new molecular targets for prevention of sudden sensorineural hearing loss.
Kalinec
F
F
Division of Cell Biology and Genetics, House Ear Institute, Los Angeles, CA 90057, USA. fkalinec@hei.org
Webster
P
P
Maricle
A
A
Guerrero
D
D
Chakravarti
D N
DN
Chakravarti
B
B
Gellibolian
R
R
Kalinec
G
G
D000818:Animals; D017305:Annexin A1 / Q000187:drug effects* / Q000378:metabolism; D003051:Cochlea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D016503:Drug Delivery Systems; D005938:Glucocorticoids / Q000494:pharmacology*; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000494:pharmacology; D008853:Microscopy; D024462:Myosin Type II / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D017305:Annexin A1; D005938:Glucocorticoids; D044042:Receptors, Formyl Peptide; D003907:Dexamethasone; D011239:Prednisolone; D024462:Myosin Type II; D006854:Hydrocortisone