Microrna-224 regulates pentraxin 3, a component of the humoral arm of innate immunity, in inner ear inflammation

摘要

MicroRNAs (miRNAs) are regulators of differentiation and development of inner ear cells. Mutations in miRNAs lead to deafness in humans and mice. Among inner ear pathologies, inflammation may lead to structural and neuronal defects and eventually to hearing loss and vestibular dysfunction.While the genetic factors of these pathways have not been defined, autoimmunity participates in these processes. We report that inflammatory stimuli in the inner ear induce activation of the innate immune system via miR-224 and pentraxin 3 (Pt×3). miR-224 is a transcriptional target of nuclear factor kB, a key mediator of innate immunity. Pt×3 is a regulator of the immune response. It is released in response to inflammation and regulated by nuclear factor kB. We show that miR-224 and Pt×3 are expressed in the inner ear and we demonstrate that miR-224 targets Pt×3. As a model of the innate immune response, we injected lipopolysaccharide into the scala tympani of mouse inner ears. This resulted in changes in the levels of miR-224 and Pt×3, in addition to activation of thecomplement system, as measured by immune cell infiltration and activated C3. This suggests that while miR-224 regulates Pt×3 under normal conditions, upon inflammation, both are recruited to offer a front line of defense in acting as responders to inflammation in the inner ear. miR-224 diminishes the innate immune response by downregulating Pt×3 expression, while Pt×3 stimulates the innate immune response. An understanding of the molecular components of the inflammatory pathway may help develop therapeutics for reducing inflammation associated with inner ear injury.