PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- production

Rhiannon B. Werder, Jason P. Lynch, Jennifer C. Simpson, Vivian Zhang, Nick H. Hodge, Matthew Poh, Elizabeth Forbes-Blom, Christina Kulis, Mark L. Smythe, John W. Upham, Kirsten Spann, Mark L. Everard, Simon Phipps

Research output: Contribution to journalArticle

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Abstract

Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon- (IFN-) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN- production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

Original languageEnglish
Article numbereaao0052
JournalScience Translational Medicine
Volume10
Issue number440
DOIs
Publication statusPublished - 9 May 2018

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Viral Bronchiolitis
Prostaglandin D2
Interferons
Respiratory Syncytial Viruses
Asthma
Bronchiolitis
prostaglandin R2 D-isomerase
Epithelial Cells
Respiratory Syncytial Virus Infections
Interleukins
Viral Load
Antiviral Agents
Cell Culture Techniques
Inflammation
Morbidity
Gene Expression
prostaglandin D2 receptor

Cite this

Werder, R. B., Lynch, J. P., Simpson, J. C., Zhang, V., Hodge, N. H., Poh, M., ... Phipps, S. (2018). PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- production. Science Translational Medicine, 10(440), [eaao0052]. https://doi.org/10.1126/scitranslmed.aao0052
Werder, Rhiannon B. ; Lynch, Jason P. ; Simpson, Jennifer C. ; Zhang, Vivian ; Hodge, Nick H. ; Poh, Matthew ; Forbes-Blom, Elizabeth ; Kulis, Christina ; Smythe, Mark L. ; Upham, John W. ; Spann, Kirsten ; Everard, Mark L. ; Phipps, Simon. / PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- production. In: Science Translational Medicine. 2018 ; Vol. 10, No. 440.
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Werder, RB, Lynch, JP, Simpson, JC, Zhang, V, Hodge, NH, Poh, M, Forbes-Blom, E, Kulis, C, Smythe, ML, Upham, JW, Spann, K, Everard, ML & Phipps, S 2018, 'PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- production' Science Translational Medicine, vol. 10, no. 440, eaao0052. https://doi.org/10.1126/scitranslmed.aao0052

PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- production. / Werder, Rhiannon B.; Lynch, Jason P.; Simpson, Jennifer C.; Zhang, Vivian; Hodge, Nick H.; Poh, Matthew; Forbes-Blom, Elizabeth; Kulis, Christina; Smythe, Mark L.; Upham, John W.; Spann, Kirsten; Everard, Mark L.; Phipps, Simon.

In: Science Translational Medicine, Vol. 10, No. 440, eaao0052, 09.05.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- production

AU - Werder, Rhiannon B.

AU - Lynch, Jason P.

AU - Simpson, Jennifer C.

AU - Zhang, Vivian

AU - Hodge, Nick H.

AU - Poh, Matthew

AU - Forbes-Blom, Elizabeth

AU - Kulis, Christina

AU - Smythe, Mark L.

AU - Upham, John W.

AU - Spann, Kirsten

AU - Everard, Mark L.

AU - Phipps, Simon

PY - 2018/5/9

Y1 - 2018/5/9

N2 - Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon- (IFN-) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN- production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

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