Nrf2 orchestrates transition from acute to chronic otitis media through inflammatory macrophages
Wenyan Fan1, Hongming Xu1, Chenling Shen1
1Department of Otolaryngology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Introduction:
Acute and chronic otitis media (AOM and COM) are common middle ear infections that can lead to hearing loss and other complications. Recent research has shown that both macrophages and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway are involved in the immune response to and the resolution of otitis media. However, the specific effects of Nrf2 on macrophages in the transition of AOM to COM are not well understood, and a practical approach to prevent this transition by targeting Nrf2/macrophages has not been established.
Methods:
In an AOM mouse model using lipopolysaccharide (LPS) injection into the middle ear, middle ear effusion (OME)-macrophages were isolated and analyzed for Nrf2 expression. M2-like polarization of macrophages was induced by Nrf2 activation and its effects on inflammatory resolution were studied by examining inflammatory neutrophils and macrophages, proinflammatory cytokines, and oxidative levels. The survival of human middle ear epithelial cells (HMMECs) co-cultured with Nrf2-modified macrophages was also evaluated. Furthermore, restoration of Nrf2 in macrophages with adeno-associated virus (AAV) vectors was performed to determine the effect on the transition of AOM to COM in experimental mice.
Results:
Reduced Nrf2 in OME-macrophages during the recovery phase was associated with uncured AOM or its development into COM, demonstrated by persistent increases in inflammatory neutrophils and macrophages, proinflammatory cytokines, and oxidative levels. Nrf2 activation induced M2-like polarization of macrophages, which improved the survival of co-cultured HMMECs treated with LPS in vitro. Restoration of Nrf2 in OME-derived low-Nrf2-expressing macrophages with AAV vectors significantly inhibited the transition of AOM to COM in experimental mice.
Discussion:
Nrf2 in macrophages plays a critical role in the immune response to and resolution of otitis media Restoration of Nrf2 expression in OME-macrophages could be a promising therapeutic approach to prevent the development of COM in AOM patients.
Insights
Restoring nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages can prevent acute otitis media from progressing to chronic otitis media. This Nrf2-macrophage pathway is key for immune response and healing in middle ear infections.
Area of Science:
- Otolaryngology
- Immunology
- Molecular Biology
Background:
- Acute and chronic otitis media (AOM and COM) are prevalent middle ear infections with potential hearing loss complications.
- Macrophages and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway are implicated in otitis media's immune response and resolution.
- The precise role of Nrf2 in macrophage function during the AOM to COM transition remains unclear, with no established therapeutic strategies targeting this pathway.
Purpose of the Study:
- To investigate the role of Nrf2 in macrophages during the transition from acute otitis media (AOM) to chronic otitis media (COM).
- To explore the potential of targeting the Nrf2/macrophage pathway as a therapeutic strategy for preventing COM development.
Main Methods:
- Established a lipopolysaccharide (LPS)-induced AOM mouse model.
- Isolated and analyzed middle ear effusion (OME)-macrophages for Nrf2 expression.
- Investigated Nrf2 activation-induced M2-like macrophage polarization and its impact on inflammation and cell survival.
- Utilized adeno-associated virus (AAV) vectors to restore Nrf2 expression in macrophages to assess its effect on AOM to COM transition.
Main Results:
- Reduced Nrf2 expression in OME-macrophages correlated with persistent inflammation and progression from AOM to COM.
- Nrf2 activation promoted M2-like macrophage polarization, enhancing the survival of human middle ear epithelial cells (HMMECs) in vitro.
- Restoring Nrf2 in low-Nrf2 macrophages using AAV vectors significantly inhibited the transition of AOM to COM in vivo.
Conclusions:
- Nrf2 within macrophages is crucial for effective immune responses and resolution of otitis media.
- Restoring Nrf2 expression in OME-macrophages presents a promising therapeutic avenue for preventing COM development in patients with AOM.
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