The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation
Open Access
- 7 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (2), 1-12
- https://doi.org/10.1038/s41419-021-03446-9
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-1 beta from P1 to P5. In the IL-1 beta -treated animals, we observed the upregulation of Tlr3, IL-1 beta, IFN-beta, Ccl2, and Cxcl10 in both PDGFR alpha+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFR alpha+ 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.This publication has 40 references indexed in Scilit:
- Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitroBrain, Behavior, and Immunity, 2013
- Nucleic acid driven sterile inflammationClinical Immunology, 2013
- Maternal immune activation by poly(I:C) induces expression of cytokines IL-1β and IL-13, chemokine MCP-1 and colony stimulating factor VEGF in fetal mouse brainJournal of Neuroinflammation, 2012
- Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammationProceedings of the National Academy of Sciences of the United States of America, 2012
- Toll‐like receptors 2 and 3 agonists differentially affect oligodendrocyte survival, differentiation, and myelin membrane formationJournal of Neuroscience Research, 2011
- Phenotypic Changes, Signaling Pathway, and Functional Correlates of GPR17-expressing Neural Precursor Cells during Oligodendrocyte DifferentiationOnline Journal of Public Health Informatics, 2011
- Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced deathGlia, 2010
- Toll-Like Receptor 3 Is a Negative Regulator of Embryonic Neural Progenitor Cell ProliferationJournal of Neuroscience, 2008
- Toll-Like Receptor 3 Is a Potent Negative Regulator of Axonal Growth in MammalsJournal of Neuroscience, 2007
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001