ERK2‐dependent activation of c‐Jun is required for nontypeable H. influenzae‐induced Cxcl2 up‐regulation in the inner ear fibrocytes

Abstract

The inner ear, composed of the cochlea and the vestibule, is a specialized sensory organ for hearing and balance. Although the inner ear has been known as an immune‐privileged organ, there is emerging evidence indicating an active immune reaction of the inner ear. Inner ear inflammation can be induced by the entry of pro‐inflammatory molecules derived from middle ear infection. Since middle ear infection is highly prevalent in children, middle ear infection‐induced inner ear inflammation can impact the normal development of language and motor coordination. Previously, we have demonstrated that the inner ear fibrocytes (spiral ligament fibrocytes) are able to recognize nontypeable H. influenzae (NTHi), a major otitis media pathogen, and up‐regulate a monocyte‐attracting chemokine through TLR2‐dependent NF‐κB activation. Here, we aimed to determine molecular mechanism involved in NTHi‐induced cochlear infiltration of polymorphonuclear cells (PMNs). The spiral ligament fibrocytes (SLFs) were found to release Cxcl2 in response to NTHi via activation of c‐Jun, not NF‐κB, leading to PMN recruitment to the cochlea. We also demonstrated that MEK1/ERK2 signaling pathway is required for NTHi‐induced Cxcl2 up‐regulation in the SLFs. Two AP‐1 motifs in the 5′‐flanking region of Cxcl2 appeared to function as a NTHi‐responsive element, and the proximal AP‐1 motif was found to have a higher binding affinity to NTHi‐activated c‐Jun than the distal one. Our results will enable us to better understand the molecular pathogenesis of middle ear infection‐induced inner ear inflammation. [Supported in part by NIH grants DC8696, DC5025, and DC 6276]