The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation
Abstract A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation...
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2021-02-01
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doaj-1ea4c654e3db4b379a06a82c4f236b6b2021-02-14T12:04:50ZengNature Publishing GroupCell Death and Disease2041-48892021-02-0112211210.1038/s41419-021-03446-9The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activationMarta Boccazzi0Juliette Van Steenwinckel1Anne-Laure Schang2Valérie Faivre3Tifenn Le Charpentier4Cindy Bokobza5Zsolt Csaba6Claudia Verderio7Marta Fumagalli8Shyamala Mani9Pierre Gressens10Université de Paris, Inserm UMR 1141 NeuroDiderotUniversité de Paris, Inserm UMR 1141 NeuroDiderotUniversité de Paris, Inserm UMR 1153, Centre de recherche en Epidémiologie et Statistiques (CRESS), Equipe HERAUniversité de Paris, Inserm UMR 1141 NeuroDiderotUniversité de Paris, Inserm UMR 1141 NeuroDiderotUniversité de Paris, Inserm UMR 1141 NeuroDiderotUniversité de Paris, Inserm UMR 1141 NeuroDiderotCNR Institute of Neuroscience, via Vanvitelli 32Department of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoUniversité de Paris, Inserm UMR 1141 NeuroDiderotUniversité de Paris, Inserm UMR 1141 NeuroDiderotAbstract A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.https://doi.org/10.1038/s41419-021-03446-9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marta Boccazzi Juliette Van Steenwinckel Anne-Laure Schang Valérie Faivre Tifenn Le Charpentier Cindy Bokobza Zsolt Csaba Claudia Verderio Marta Fumagalli Shyamala Mani Pierre Gressens |
spellingShingle |
Marta Boccazzi Juliette Van Steenwinckel Anne-Laure Schang Valérie Faivre Tifenn Le Charpentier Cindy Bokobza Zsolt Csaba Claudia Verderio Marta Fumagalli Shyamala Mani Pierre Gressens The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation Cell Death and Disease |
author_facet |
Marta Boccazzi Juliette Van Steenwinckel Anne-Laure Schang Valérie Faivre Tifenn Le Charpentier Cindy Bokobza Zsolt Csaba Claudia Verderio Marta Fumagalli Shyamala Mani Pierre Gressens |
author_sort |
Marta Boccazzi |
title |
The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation |
title_short |
The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation |
title_full |
The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation |
title_fullStr |
The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation |
title_full_unstemmed |
The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation |
title_sort |
immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of tlr3 activation |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-02-01 |
description |
Abstract A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation. |
url |
https://doi.org/10.1038/s41419-021-03446-9 |
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