The human placenta is a dynamic organ that modulates physiological adaptations to pregnancy. To define the immunological signature of the human placenta, we performed unbiased profiling of secreted immune factors from human chorionic villi isolated from placentas at mid and late stages of pregnancy. We show that placental trophoblasts constitutively secrete the inflammasome-associated cytokines IL-1β and IL-18, which is blocked by NLRP3 inflammasome inhibitors and occurs without detectable gasdermin D cleavage. We further show that placenta-derived IL-1β primes monocytes for inflammasome induction to protect against Listeria monocytogenes infection. Last, we show that the human placenta responds to L. monocytogenes infection through additional inflammasome activation and that inhibition of this pathway sensitizes villi to infection. Our results thus identify the inflammasome as an important mechanism by which the human placenta regulates systemic and local immunity during pregnancy to defend against L. monocytogenes infection.
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4 January 2021
Article|
September 25 2020
Inflammasome signaling in human placental trophoblasts regulates immune defense against Listeria monocytogenes infection
Christina Megli,
Christina Megli
Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
1
Division of Maternal-Fetal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
2
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical School, Pittsburgh, PA
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Stefanie Morosky,
Stefanie Morosky
Investigation
3
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
4
Center for Microbial Pathogenesis, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
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Dhivyaa Rajasundaram,
Dhivyaa Rajasundaram
Formal analysis, Resources, Software, Visualization, Writing - original draft, Writing - review & editing
3
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Carolyn B. Coyne
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
2
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical School, Pittsburgh, PA
3
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
4
Center for Microbial Pathogenesis, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
Correspondence to Carolyn B. Coyne: coynec2@pitt.edu
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Christina Megli
Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
1
Division of Maternal-Fetal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
2
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical School, Pittsburgh, PA
Stefanie Morosky
Investigation
3
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
4
Center for Microbial Pathogenesis, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
Dhivyaa Rajasundaram
Formal analysis, Resources, Software, Visualization, Writing - original draft, Writing - review & editing
3
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
Carolyn B. Coyne
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
2
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical School, Pittsburgh, PA
3
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
4
Center for Microbial Pathogenesis, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
Correspondence to Carolyn B. Coyne: coynec2@pitt.edu
Received:
April 07 2020
Revision Received:
July 06 2020
Accepted:
August 20 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Children's Hospital of Pittsburgh
(NO AWARD)
Magee-Womens Research Institute
(4032)
Medical Center, University of Pittsburgh
(P30CA047904)
National Institutes of Health
(AI145828, HD097400)
© 2020 Megli et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (1): e20200649.
Article history
Received:
April 07 2020
Revision Received:
July 06 2020
Accepted:
August 20 2020
Connected Content
Citation
Christina Megli, Stefanie Morosky, Dhivyaa Rajasundaram, Carolyn B. Coyne; Inflammasome signaling in human placental trophoblasts regulates immune defense against Listeria monocytogenes infection. J Exp Med 4 January 2021; 218 (1): e20200649. doi: https://doi.org/10.1084/jem.20200649
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