The inner ear is a complex and delicate structure comprising the cochlea and the vestibular system. The cochlea, which enables hearing in humans, must be maintained in a strict homeostasis to function (1). Several congenital and acquired defects in the cochlea cause hearing loss (2-4). Although the incidence does not frequently occur, infective disorders, e.g. otitis media, labyrinthitis, can irreversibly damage the core auditory structure, named the organ of Corti, and cause life-long hearing loss (5). A proper immune response against infection, thus, is crucial for preserving the auditory function. The inner ear had long been considered an ‘immune-privileged’ structure with the eyes and brain. However, recent studies revealed that immune cells, specifically macrophages, are within the mesenchymal region of the cochlea, namely the stria vascularis and the spiral ligament in the lateral wall (6-8). Such immunity can thus protect the inner ear from pathogens as well as from the endogenous toxins. However, since excessive immune reaction can easily damage the normal archi-tecture within the inner ear, the immune response should be fine regulated. Recently, we reported a protein selectively localized in the inner ear during bacterial infection, named cochlin, as a possible mediator of such regulation (8). In this review, the immunological function of cochlin and the mechanism behind its role within the inner ear immunity are summarized.
Cochlin, as implied by its name, is abundantly expressed in the cochlea and the vestibule of the inner ear; additionally, in the lymphoid organs including the lymph and spleen (9, 10). Robertson
The structure of cochlin is divided into two parts, the LCCL domain at the N-terminus and the two vWFA domains at the other end (Fig. 1) (10). The LCCL domain, commonly present in the
The two parts of cochlin are cleaved by a member of the metalloprotease family, named aggrecanase 1 (8, 13). Py
Previous research illuminated the role of splenic cochlin as the mediator of innate immunity (13). The study found that cochlin was specifically secreted by the follicular dendritic cells within the spleen and was stored in the surrounding ECM called a conduit. As a response to
We showed that the baseline auditory function between the wild type mice and Coch knock-out mice did not differ significantly (8). However, following the PA infection, the Coch knock-out mice showed greater hearing loss compared to the wild type mice. Thus, we suggested that cochlin’s auditory protection may be linked to its anti-bacterial action. Also, we specified that cleaved LCCL domain is the mediator of such protective role. LCCL within the perilymph of
We elucidated two main mechanisms by which LCCL released in scala tympani regulates immune response (Fig. 2) (8). First, LCCL recruits innate immune cells by increasing the expression of pro-inflammatory cytokines such as IL-1β and IL-6. The infiltrations of neutrophils and macrophages were increased in the wild type mice, compared to those in the Coch knock-out mice. Specifically, the number of monocyte-derived macrophages distinsuished from resident macrophages based on morphology, significantly increased in the wild type mice. This implies that the recruitment of the innate immune cells within the blood vessels is facilitated by the LCCL. Addi-tionally, we found that LCCL physically interacts with the pathogen. Previous studies reported that LCCL do not directly interact with neither bacterial molecules such as LPS, pattern recognition peptidoglycans, nor the bacteria (13, 17). Our study also found that the viability of PA was not impacted by the addition of the recombinant LCCL peptide
In this review, we discussed the immunological role of the cochlin and how the innate immunity within the inner ear is delicately controlled by the cochlin. The LCCL domain is cleaved from the full-length cochlin by aggrecanase I after infection. The LCCL domain then acts as a systemic modulator of innate immunity by up-regulating the expression of pro-inflammatory cytokines such as IL-1β and IL-6. In the inner ear, the LCCL controls the range of inflammation by physically entrapping pathogens as well as inducing the recruitment of innate immune cells. In conclusion, cochlin, long known to be linked with auditory function, protects the core sensory structure from infection by inducing the needed immunity while limiting excessive inflammatory damage.
Cochlin is currently studied in various areas of medicine. It is linked with glaucoma, autoimmune disease of the inner ear, as well as the DFNA9 syndrome mentioned above (18, 19). Since the exact mechanisms how such defects occur are elusive, further research must be conducted. The clinical use of cochlin is currently very limited. Ikezono
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (2019R 1A2C2008481 to Y.-M.H.)
The authors have no conflicting interests.