Overexpression of immune-responsive gene 1 prevents acute otitis media due to streptococcus pneumoniae infection through Nrf2- Hmox1 pathway

Abstract

Background: Acute otitis media (AOM) is one of the most commonly diagnosed childhood diseases that are associated with influenza infection. Immunoresponsive gene 1 (Irg1) is overexpressed in mammalian macrophage during inflammation process. Here, the present study aims to investigate the role of Irg1 in streptococcus pneumoniae infection-induced inflammatory response in AOM through Nrf2 signaling pathway. Methods: Positive rate of streptococcus pneumoniae and expression of Irg1, Nrf2 and Hmox1 were determined in the middle ear lavage fluid from 85 AOM patients infected with streptococcus pneumoniae and 48 healthy subjects. After the successful establishment of mice model with AOM, macrophage was harvest from the middle ear lavage fluid of mice. At last, to investigate the effect of Irg1 and Nrf2 signaling pathway on inflammatory response and streptococcus pneumoniae infection by accumulating macrophage, Irg1, sh-Irg1 and retinoic acid (an inhibitor of Nrf2 signaling pathway) were injected into AOM mice. Results: Irg1 exhibited a high level and activated Nrf2 signaling pathway was detected in AOM. Besides, positive rate of streptococcus pneumoniae was increased in AOM. Furthermore, in the mice model with AOM, Irg1 could repress inflammatory response by downregulating expression of TNF-α, IL-6 and IL-1β and inhibit streptococcus pneumoniae infection by stimulating accumulation of macrophage to increase its endocytosis through activation of Nrf2 signaling pathway. Conclusion: Taken together, Irg1 contributes to inhibiting inflammatory response and streptococcus pneumoniae infection in AOM by promoting accumulation of macrophage through activation of Nrf2 signaling pathway, which provides novel therapeutic targets for AOM therapy.