IRAK-M regulates NTHi-induced inflammation via JNK and NF-κB signal pathways

Nontypeable Haemophilus influenzae (NTHi) is a causative agent of acute exacerbations in chronic lung conditions. Despite antibiotic administration, unresolved hyperinflammation underscores the urgent need to identify host-directed immunomodulatory targets. The bronchial mucosa serves as a primary site for infection initiation and propagation. This study aims to investigate the role of airway-expressed interleukin-1 receptor-associated kinase M (IRAK-M) in modulating NTHi-induced lung inflammation and its potential mechanisms.

We examined the expression of IRAK-M and TLR4 in lung epithelial cells and macrophages following NTHi infection. IRAK-M was silenced or overexpressed to assess its impact on cytokine production. In vitro investigations, JNK and NF-κB inhibitors were applied to test whether IRAK-M-mediated inflammation was partly dependent on these pathways. In vivo, the effects of JNK and NF-κB inhibitors were evaluated in NTHi-infected mice.

NTHi infection upregulated IRAK-M and TLR4 expression in both lung epithelial cells and macrophages. Upon NTHi stimulation, inflammatory responses were enhanced by IRAK-M overexpression or suppressed by IRAK-M silencing in lung-resident and immune cells. IRAK-M overexpression led to overactivation of JNK and NF-κB pathways. Inhibition of these pathways counteracted IRAK-M-induced inflammatory responses. In vivo, JNK and NF-κB inhibitors alleviated lung inflammation, and JNK inhibitors improved survival in NTHi-infected mice.

IRAK-M regulates NTHi-induced inflammation possibly through NF-κB and JNK signaling pathways. Modulation of IRAK-M and its downstream JNK and NF-κB signaling pathways might represent a novel therapeutic strategy for controlling NTHi-induced inflammation.