Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll‐like receptors 4 and 7/8 in murine and human lungs

Sayers, Ian; Thakker, Dhruma; Billington, Charlotte; Kreideweiss, Stefan; Grundl, Marc A.; Bouyssou, Thierry; Thamm, Sven; Kreuz, Sebastian; Hall, Ian P.

Abstract

Background and Purpose: Toll‐like receptors 4 (TLR4) and TLR7/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is an important regulator of signalling by toll‐like receptor (TLR) and hence is a potential therapeutic target in diseases characterized by increased lung inflammatory signalling. Experimental Approach: We used an established murine model of acute lung inflammation, and studied human lung tissue ex vivo, to investigate the effects of inhibiting IRAK4 on lung inflammatory pathways. Key Results: We show that TLR4 stimulation produces an inflammatory response characterized by neutrophil influx and tumour necrosis factor‐α (TNF‐α) production in murine lungs and that these responses are markedly reduced in IRAK4 kinase‐dead mice. In addition, we characterize a novel selective IRAK4 inhibitor, BI1543673, and show that this compound can reduce lipopolysaccharide (LPS)‐induced airway inflammation in wild‐type mice. Additionally, BI1543673 reduced inflammatory responses to both TLR4 and TLR7/8 stimulation in human lung tissue studied ex vivo. Conclusion and Implications: These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7/8.

Citation

Sayers, I., Thakker, D., Billington, C., Kreideweiss, S., Grundl, M. A., Bouyssou, T., Thamm, S., Kreuz, S., & Hall, I. P. (2024). Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll‐like receptors 4 and 7/8 in murine and human lungs. British Journal of Pharmacology, https://doi.org/10.1111/bph.16509

• Journal Article Type: Article
• Acceptance Date: May 23, 2024
• Online Publication Date: Aug 13, 2024
• Publication Date: Aug 13, 2024
• Deposit Date: Sep 23, 2024
• Publicly Available Date: Sep 27, 2024
• Journal: British Journal of Pharmacology
• Print ISSN: 0007-1188
• Electronic ISSN: 1476-5381
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1111/bph.16509
• Keywords: exacerbations, lung inflammation, toll‐ like receptors, interstitial lung disease, chronic obstructive pulmonary disease, IRAK4
• Public URL: https://nottingham-repository.worktribe.com/output/38630204
• Publisher URL: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16509