title: IL-10/HMOX1 signaling modulates cochlear inflammation via negative regulation of MCP-1/CCL2 expression in cochlear fibrocytes.
abstract: Cochlear inflammatory diseases, such as tympanogenic labyrinthitis, are associated with acquired sensorineural hearing loss. Although otitis media is extremely frequent in children, tympanogenic labyrinthitis is not commonly observed, which suggests the existence of a potent anti-inflammatory mechanism modulating cochlear inflammation. In this study, we aimed to determine the molecular mechanism involved in cochlear protection from inflammation-mediated tissue damage, focusing on IL-10 and hemoxygenase-1 (HMOX1) signaling. We demonstrated that IL-10Rs are expressed in the cochlear lateral wall of mice and rats, particularly in the spiral ligament fibrocytes (SLFs). The rat SLF cell line was found to inhibit nontypeable Haemophilus influenzae (NTHi)-induced upregulation of monocyte chemotactic protein-1 (MCP-1; CCL2) in response to IL-10. This inhibition was suppressed by silencing IL-10R1 and was mimicked by cobalt Protoporphyrin IX and CO-releasing molecule-2. In addition, IL-10 appeared to suppress monocyte recruitment through reduction of NTHi-induced rat SLF cell line-derived chemoattractants. Silencing of HMOX1 was found to attenuate the inhibitory effect of IL-10 on NTHi-induced MCP-1/CCL2 upregulation. Chromatin immunoprecipitation assays showed that IL-10 inhibits NTHi-induced binding of p65 NF-κB to the distal motif in the promoter region of MCP-1/CCL2, resulting in suppression of NTHi-induced NF-κB activation. Furthermore, IL-10 deficiency appeared to significantly affect cochlear inflammation induced by intratympanic injections of NTHi. Taken together, our results suggest that IL-10/HMOX1 signaling is involved in modulation of cochlear inflammation through inhibition of MCP-1/CCL2 regulation in SLFs, implying a therapeutic potential for a CO-based approach for inflammation-associated cochlear diseases.
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;
authors.forename: Jeong-Im
authors.initials: JI
authors.lastname: Woo
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Kil
authors.affiliation: Division of Clinical and Translational Research, House Research Institute, Los Angeles, CA 90057; and.
authors.forename: Sejo
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749, South Korea.
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; skmoon@mednet.ucla.edu.
authors.forename: Sung K
authors.initials: SK
authors.lastname: Moon
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000276:immunology*; D003051:Cochlea / Q000276:immunology* / Q000473:pathology; D015834:Cochlear Diseases / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology*; D006419:Heme Oxygenase (Decyclizing) / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology
chemical_list: C491768:Ccl2 protein, mouse; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C556062:IL10 protein, mouse; D008565:Membrane Proteins; C498144:Rela protein, mouse; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D016753:Interleukin-10; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C491523:Hmox1 protein, rat