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IRAK4 is a critical regulator of inflammatory signalling through Toll like receptors (TLR) 4 and 7/8 in murine and human lungs
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  • Ian SAYERS,
  • Dhruma Thakker,
  • Charlotte Billington,
  • Stefan Kreideweiss,
  • Marc Grundl,
  • Thierry Bouyssou,
  • Sven Thamm,
  • Sebastian Kreuz,
  • IAN HALL
Ian SAYERS
University of Nottingham
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Dhruma Thakker
University of Nottingham
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Charlotte Billington
University of Nottingham
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Stefan Kreideweiss
Boehringer Ingelheim Pharmaceutical Research and Development Centre Biberach
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Marc Grundl
Boehringer Ingelheim Pharmaceutical Research and Development Centre Biberach
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Thierry Bouyssou
Boehringer Ingelheim Pharmaceutical Research and Development Centre Biberach
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Sven Thamm
Boehringer Ingelheim Pharmaceutical Research and Development Centre Biberach
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Sebastian Kreuz
Boehringer Ingelheim Pharmaceutical Research and Development Centre Biberach
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IAN HALL
University of Nottingham

Corresponding Author:[email protected]

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Abstract

Background and purpose: Toll like receptors (TLR) 4 and 7/8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. IRAK4 is an important regulator of TLR signalling, and hence is a potential therapeutic target in diseases characterised 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 characterised by neutrophil influx and TNFα production in murine lungs, and that these responses are markedly reduced in IRAK4 kinase-dead mice. In addition, we characterise a novel selective IRAK4 inhibitor, BI1543673 and show that this compound is able to reduce LPS induced airway inflammation in wild type mice. BI1543673 also reduced inflammatory responses to both TLR4 and TLR 7/8 stimulation in human lung tissue studied ex vivo. Conclusions and implications: These data show demonstrate a key role for IRAK4 signalling in lung inflammation, and suggest that IRAK4 inhibition has potential utility for treating lung diseases characterised by inflammatory responses driven through TLR4 and TLR 7/8.
07 Feb 2024Review(s) Completed, Editorial Evaluation Pending
08 May 20241st Revision Received
08 May 2024Submission Checks Completed
08 May 2024Assigned to Editor
08 May 2024Reviewer(s) Assigned