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Intra-tracheal Administration of Haemophilus influenzae in Mouse Models to Study Airway Inflammation
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PYHIN1 regulates pro-inflammatory cytokine induction rather than innate immune DNA sensing in airway epithelial cells

Davide Massa1, Marcin Baran1, Jose A Bengoechea2

  • 1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

The Journal of Biological Chemistry
|February 28, 2020
PubMed

Insights

Airway epithelial cells detect DNA viruses through cGAS-STING pathways, but PYHIN1 protein primarily induces inflammation via IL-1 and TNFα signaling, not direct DNA sensing.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Animal cells utilize pattern-recognition receptors (PRRs) to detect pathogens and initiate immune responses like interferon and cytokine induction.
  • Intracellular PRR-signaling pathways, including cGMP-AMP synthase (cGAS) and PYHIN protein IFI16 signaling via STING, are known for detecting DNA viruses in myeloid cells.
  • The response of airway epithelial cells to DNA viruses and the function of PYHIN proteins in these cells remain largely uncharacterized.

Purpose of the Study:

  • To investigate the expression and activity of cGAS, STING, and PYHIN proteins in human lung epithelial cells.
  • To determine the role of these proteins in the innate immune response of airway epithelial cells to DNA viruses.
  • To elucidate the specific functions of PYHIN proteins, particularly PYHIN1, in airway epithelial cell signaling.

Main Methods:

  • Analysis of cGAS, STING, and PYHIN protein expression in human lung epithelial cell lines (A549 and NuLi-1).
  • Functional assays to assess DNA sensing and downstream signaling in response to DNA stimulation.
  • Investigation of PYHIN1 activity, including its interaction with IL-1 and TNFα, and its effect on gene transcription.

Main Results:

  • A549 cells, lacking STING, did not respond to DNA; ectopic STING expression restored a cGAS-dependent DNA response.
  • NuLi-1 cells expressed STING, which mediated DNA-dependent gene induction upon stimulation.
  • PYHIN1, present in both cell types, did not act as a DNA sensor but directly induced IL-6 and TNFα transcription in response to IL-1 or TNFα stimulation.

Conclusions:

  • Airway epithelial cells possess functional cGAS-STING pathways for DNA virus detection, contingent on STING expression.
  • PYHIN proteins, specifically PYHIN1, play a distinct role in inducing proinflammatory cytokines in airway epithelial cells, independent of direct viral DNA sensing.
  • PYHIN1's HIN domain is crucial for mediating the induction of IL-6 and TNFα transcription, highlighting its role in inflammatory responses.
Keywords:
DNA sensingDNA virusesPYHIN proteinsSTINGairway epithelial cellscGASinnate immunityinterleukin 6 (IL-6)pattern recognition receptor (PRR)tumor necrosis factor (TNF)

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