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Platelet activating factor receptor regulates colitis-induced pulmonary inflammation through the NLRP3 inflammasome

Mucosal Immunology (2019) | Download Citation

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Abstract

Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1β levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1β in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.

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Acknowledgements

The authors acknowledge support from the bioresource unit at the University of Newcastle and Hunter Medical Research Institute (HMRI). This work was supported by National Health and Medical Research Council (NHMRC) of Australia, Cancer Institute NSW and a Bowel of the Ball project grant from HMRI.

Author information

Affiliations

  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia

    • Gang Liu
    • , Sean W. Mateer
    • , Bridie J. Goggins
    • , Hock Tay
    • , Andrea Mathe
    • , Kening Fan
    • , Rachel Neal
    • , Jessica Bruce
    • , Grace Burns
    • , Kyra Minahan
    • , Paul S. Foster
    • , Philip M. Hansbro
    •  & Simon Keely
  2. Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

    • Gang Liu
    • , Sean W. Mateer
    • , Alan Hsu
    • , Bridie J. Goggins
    • , Hock Tay
    • , Andrea Mathe
    • , Kening Fan
    • , Rachel Neal
    • , Jessica Bruce
    • , Grace Burns
    • , Kyra Minahan
    • , Steven Maltby
    • , Michael Fricker
    • , Paul S. Foster
    • , Peter A. B. Wark
    • , Philip M. Hansbro
    •  & Simon Keely
  3. Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia

    • Gang Liu
    • , Sean W. Mateer
    • , Bridie J. Goggins
    • , Andrea Mathe
    • , Kening Fan
    • , Rachel Neal
    • , Jessica Bruce
    • , Grace Burns
    • , Kyra Minahan
    •  & Simon Keely
  4. School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia

    • Alan Hsu
    • , Michael Fricker
    •  & Peter A. B. Wark
  5. School of Nursing and Midwifery, University of Newcastle, Callaghan, NSW, Australia

    • Steven Maltby

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Contributions

S.K. and G.L. participated in the design of the concept, hypothesis and aims of the study and drafting of the manuscript. G.L. performed in vivo experiments. G.L., A.H., J.B., and G.B. performed in vitro and molecular experiments. A.M., B.G., K.M., K.F., and R.N assisted with mouse experiments. H.T. assisted flow cytometry analysis. M.F., and S.M. assisted with data analysis. P.F., P.W., and P.M.H. assisted with concept, experimental design and manuscript editing. All the authors read and approved the final manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Simon Keely.

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DOI

https://doi.org/10.1038/s41385-019-0163-3