The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia

Jie Liao; Vishal S. Kapadia; L. Steven Brown; Naeun Cheong; Christopher Longoria; Dan Mija; Mrithyunjay Ramgopal; Julie Mirpuri; Donald C. McCurnin; Rashmin C. Savani

doi:10.1038/ncomms9977

The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia

Jie Liao, Vishal S. Kapadia, L. Steven Brown, Naeun Cheong, Christopher Longoria, Dan Mija, Mrithyunjay Ramgopal, Julie Mirpuri, Donald C. McCurnin, Rashmin C. Savani

Research output: Contribution to journal › Article › peer-review

114 Scopus citations

Abstract

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3 / mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.

Original language	English (US)
Article number	8977
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9977
State	Published - Nov 27 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms9977

Cite this

@article{e1eaf9d893b44dc1a61ca79febd4352e,

title = "The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia",

abstract = "The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3 / mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.",

author = "Jie Liao and Kapadia, {Vishal S.} and Brown, {L. Steven} and Naeun Cheong and Christopher Longoria and Dan Mija and Mrithyunjay Ramgopal and Julie Mirpuri and McCurnin, {Donald C.} and Savani, {Rashmin C.}",

note = "Funding Information: We thank Dr Vishva M. Dixit (Genentech, San Francisco, CA) for the gift of the Nlrp3−/− mice. We also thank the personnel that supported the Bronchopulmonary Dysplasia (BPD) Resource Center: the animal husbandry group led by Drs D. Carey and M. Leland; the neonatal intensive care unit staff (H. Martin, S. Ali, D. Correll, L. Kalisky, L. Nicley, R. Degan, S. Gamez); the Wilford Hall Medical Center neonatal fellows and D. Catland, who assisted in the care of the animals; the University of Texas Health Science Center San Antonio pathology staff (L. Buchanan, H. Dixon, A. Schreiner), who performed necropsies and obtained biological specimens; and Vicki Winter for administrative support. We also thank the patients, families and staff of the Neonatal Intensive Care Unit at Parkland Health and Hospital System for their care of the infants included in this study and for providing samples for analysis. This work was supported by grants R01 HL963535 and U01 HL075900 from the National Institutes of Health, and by grants from The Children{\textquoteright}s Medical Center Foundation, Dallas, TX to R.C.S. Additional support was provided by NIH Grants HL-52636 (BPD Resource Center) and P51RR13986 for facility support. We thank Drs Philip Shaul, Chieko Mineo, Ralph DeBerardenis and Lora Hooper for ongoing discussions of the project and their critical review of the manuscript.",

year = "2015",

month = nov,

day = "27",

doi = "10.1038/ncomms9977",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia

AU - Liao, Jie

AU - Kapadia, Vishal S.

AU - Brown, L. Steven

AU - Cheong, Naeun

AU - Longoria, Christopher

AU - Mija, Dan

AU - Ramgopal, Mrithyunjay

AU - Mirpuri, Julie

AU - McCurnin, Donald C.

AU - Savani, Rashmin C.

N1 - Funding Information: We thank Dr Vishva M. Dixit (Genentech, San Francisco, CA) for the gift of the Nlrp3−/− mice. We also thank the personnel that supported the Bronchopulmonary Dysplasia (BPD) Resource Center: the animal husbandry group led by Drs D. Carey and M. Leland; the neonatal intensive care unit staff (H. Martin, S. Ali, D. Correll, L. Kalisky, L. Nicley, R. Degan, S. Gamez); the Wilford Hall Medical Center neonatal fellows and D. Catland, who assisted in the care of the animals; the University of Texas Health Science Center San Antonio pathology staff (L. Buchanan, H. Dixon, A. Schreiner), who performed necropsies and obtained biological specimens; and Vicki Winter for administrative support. We also thank the patients, families and staff of the Neonatal Intensive Care Unit at Parkland Health and Hospital System for their care of the infants included in this study and for providing samples for analysis. This work was supported by grants R01 HL963535 and U01 HL075900 from the National Institutes of Health, and by grants from The Children’s Medical Center Foundation, Dallas, TX to R.C.S. Additional support was provided by NIH Grants HL-52636 (BPD Resource Center) and P51RR13986 for facility support. We thank Drs Philip Shaul, Chieko Mineo, Ralph DeBerardenis and Lora Hooper for ongoing discussions of the project and their critical review of the manuscript.

PY - 2015/11/27

Y1 - 2015/11/27

N2 - The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3 / mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.

AB - The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3 / mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.

UR - http://www.scopus.com/inward/record.url?scp=84948708402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84948708402&partnerID=8YFLogxK

U2 - 10.1038/ncomms9977

DO - 10.1038/ncomms9977

M3 - Article

C2 - 26611836

AN - SCOPUS:84948708402

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8977

ER -

The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this