Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov;181(22):4647-4657.
doi: 10.1111/bph.16509. Epub 2024 Aug 13.

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

Ian Sayers  1 , Dhruma Thakker  1 , Charlotte Billington  1 , Stefan Kreideweiss  2 , Marc A Grundl  2 , Thierry Bouyssou  2 , Sven Thamm  2 , Sebastian Kreuz  2 , Ian P Hall  1
Affiliations
Free article

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

Ian Sayers et al. Br J Pharmacol. 2024 Nov.
Free article

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.

Keywords: IRAK4; chronic obstructive pulmonary disease; exacerbations; interstitial lung disease; lung inflammation; toll‐ like receptors.

PubMed Disclaimer

References

REFERENCES

    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Ostrom, R., Papapetropoulos, A., … Wong, S. S. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. British Journal of Pharmacology, 180, S289–S373. https://doi.org/10.1111/bph.16181
    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Beuve, A., Brouckaert, P., Bryant, C., Burnett, J. C., Farndale, R. W., Friebe, A., Garthwaite, J., Hobbs, A. J., Jarvis, G. E., … Waldman, S. A. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors. British Journal of Pharmacology, 180, S241–S288. https://doi.org/10.1111/bph.16180
    1. Bothe, U., Günther, J., Nubbemeyer, R., Siebeneicher, H., Ring, S., Bömer, U., Peters, M., Rausch, A., Denner, K., Himmel, H., Sutter, A., Terebesi, I., Lange, M., Wengner, A. M., Guimond, N., Thaler, T., Platzek, J., Eberspächer, U., Schäfer, M., … Schmidt, N. (2024). Discovery of IRAK4 inhibitors BAY1834845 (zabedosertib) and BAY1830839. Journal of Medicinal Chemistry, 67(2), 1225–1242. https://doi.org/10.1021/acs.jmedchem.3c01714
    1. Corzo, C. A., Varfolomeev, E., Setiada, A. F., Francis, R., Klabunde, S., Senger, K., Sujatha‐Bhaskar, S., Drobnick, J., Do, S., Suto, E., Huang, Z., Eastham‐Anderson, J., Katewa, A., Pang, J., Domeyer, M., Dela‐Cruz, C., Paler‐Martinez, A., Lau, V. W. C., Hadadianpour, A., … Zarrin, A. A. (2020). The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells. Science Signaling, 13(634), eaax1053. https://doi.org/10.1126/scisignal.aaz1053
    1. Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. British Journal of Pharmacology, 179, 3907–3913. https://doi.org/10.1111/bph.15868

MeSH terms

LinkOut - more resources