Abstract
Abstract Inflammatory response is commonly involved in the pathogenesis of various cochlear diseases such as acoustic trauma and cisplatin ototoxicity. Previously, we have demonstrated that the spiral ligament fibrocytes play a pivotal role in cochlear inflammation through secretion of chemokines such as CCL2 and CXCL2 in response to pro-inflammatory signals. In this study, we aim to determine molecular mechanism involved in negative modulation of cochlear inflammation. We found that IL-10 inhibits SLF’s CCL2 up-regulation and migration of THP-1 cells in response to SLF-derived molecules. The SLFs appeared to up-regulate HMOX1 expression via NRF-2 activation. The inhibitory effect of IL-10 was mimicked by CoPP and CORM-3 but was blocked by silencing of IL-10RA and HMOX1. IL-10 was found to inhibit binding of p65 NFκB to the enhancer region of the CCL2 gene. IL-10 deficiency appeared to enhance cochlear inflammation secondary to nontypeable H. influenzae-induced otitis media. Furthermore, we demonstrated that the cochlear macrophages serve as a local source of IL-10, which appeared to be primarily distributed in the stria vascularis. Our results suggest that cochlear macrophage-derived IL-10 modulates cochlear inflammation by inhibition of SLF’s CCL2 up-regulation through HMOX1-mediated CO production. This study is anticipated providing us with a novel strategy for the management of inflammation-associated cochlear diseases.
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