Glucocorticoid‐stimulated, transcription‐independent release of annexin A1 by cochlear Hensen cells

Abstract

Background and purpose: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. Experimental approach: 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. Key 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 and implications: 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.

Effects of a glucocorticoid receptor agonist, dexamethasone, on fathead minnow reproduction, growth, and development

“…Chem. 31,2012In humans, dexamethasone provides its therapeutic antiinflammatory benefit by acting on specific molecular targets, including the glucocorticoid receptor annexin, prostaglandin endoperoxide synthase 1, and prostaglandin endoperoxide synthase 2 [39][40][41]. Through gene expression analyses, annexin and prostaglandin endoperoxide synthase mRNA have been identified in the ovarian tissue of various fish species, providing evidence of potential involvement of these genes in gonad differentiation and ovulation, respectively [42][43][44].…”

Protecting the auditory system with glucocorticoids

“…The effects of acute elevation of glucocorticoids in the auditory system are most probably mediated by GRs via rapid transcriptional (and possibly non-transcriptional) pathways (Kalinec et al, 2009). One of the mechanisms underlying GR-mediated protection may involve an autoregulation of the receptor.…”

Biology and pathobiology of lipid droplets and their potential role in the protection of the organ of Corti

“…In 2009, a completely different role for Hensen cell LDs was proposed by the laboratory of one of the authors of this Review (Kalinec et al, 2009). Experimental evidence indicated that Hensen cell LDs contain significant amounts of the protein annexin A1 (ANXA1), and that glucocorticoids activate a cellular mechanism that results in the release of ANXA1 from the LDs first, and then from the Hensen cells to the extracellular milieu.…”

“…Experimental evidence indicated that Hensen cell LDs contain significant amounts of the protein annexin A1 (ANXA1), and that glucocorticoids activate a cellular mechanism that results in the release of ANXA1 from the LDs first, and then from the Hensen cells to the extracellular milieu. Since ANXA1 is known to inhibit leukocyte migration and extravasation by receptor-mediated signaling, as well as to regulate cell death signaling and the phagocytic clearance of apoptotic cells (D'Acquisto et al, 2008), it was proposed that Hensen cell LDs would play a major role in preventing leukocytes from invading the organ of Corti and facilitating the resolution of inflammatory responses in the mammalian inner ear (Kalinec et al, 2009). The potential immunological and anti-inflammatory roles of LDs in the cochlea are discussed in more detail in Section 8.…”

“…For example, the protein annexin A1 was found inside the LDs of guinea pig Hensen cells (Kalinec et al, 2009), membranes and ribosomes were observed in LDs of leukocytes (Wan et al, 2007), and RNA was reported in the mast cell LD (Dvorak et al, 2003). Moreover, detection of ER membrane proteins, ER chaperones, and caveolins by immunoelectron microscopy (Bozza et al, 1997; Dvorak et al, 1992; Ghosal et al, 1994; Robenek et al, 2004) imply that LDs may have an internal structure other than a simple mass of lipid esters (Fig.…”