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Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury.

ABSTRACT: Background:The immune system of human and mouse neonates is relatively immature. However, innate lymphoid cells (ILCs), commonly divided into the subsets ILC1, ILC2, and ILC3, are already present in the placenta and other fetal compartments and exhibit higher activity than what is seen in adulthood. Recent reports have suggested the potential role of ILCs, especially ILC2s, in spontaneous preterm labor, which is associated with brain damage and subsequent long-term neurodevelopmental deficits. Therefore, we hypothesized that ILCs, and especially ILC2s, play a role in preterm brain injury. Methods:C57Bl/6J mice at postnatal day 6 were subjected to hypoxia-ischemia (HI) insult induced by left carotid artery ligation and subsequent exposure to 10% oxygen in nitrogen. The presence of ILCs and ILC2s in the brain was examined at different time points after HI. The contribution of ILC2s to HI-induced preterm brain damage was explored using a conditionally targeted ILC2-deficient mouse strain (Ror? fl/fl IL7r Cre ), and gray and white-matter injury were evaluated at 7 days post-HI. The inflammatory response in the injured brain was assessed using immunoassays and immunochemistry staining. Results:Significant increases in ILCs and ILC2s were observed at 24 h, 3 days, and 7 days post-HI in the injured brain hemisphere compared with the uninjured hemisphere in wild-type mice. ILC2s in the brain were predominantly located in the meninges of the injured ipsilateral hemispheres after HI but not in the brain parenchyma. Overall, we did not observe changes in cytokine/chemokine levels in the brains of Ror? fl/fl IL7r Cre mice compared with wild type animals apart from IL-13. Gray and white-matter tissue loss in the brain was not affected after HI in Ror? fl/fl IL7r Cre mice. Correspondingly, we did not find any differences in reactive microglia and astrocyte numbers in the brain in Ror? fl/fl IL7r Cre mice compared with wild-type mice following HI insult. Conclusion:After HI, ILCs and ILC2s accumulate in the injured brain hemisphere. However, ILC2s do not contribute to the development of brain damage in this mouse model of preterm brain injury.

SUBMITTER: Zelco A

PROVIDER: S-EPMC7426829 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury.

Zelco Aura A Rocha-Ferreira Eridan E Nazmi Arshed A Ardalan Maryam M Chumak Tetyana T Nilsson Gisela G Hagberg Henrik H Mallard Carina C Wang Xiaoyang X

Frontiers in cellular neuroscience 20200807

<h4>Background</h4>The immune system of human and mouse neonates is relatively immature. However, innate lymphoid cells (ILCs), commonly divided into the subsets ILC1, ILC2, and ILC3, are already present in the placenta and other fetal compartments and exhibit higher activity than what is seen in adulthood. Recent reports have suggested the potential role of ILCs, especially ILC2s, in spontaneous preterm labor, which is associated with brain damage and subsequent long-term neurodevelopmental def ...[more]

PMID: 32848629

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Project description:Background and aimsAlthough type 2 innate lymphoid cells (ILC2s) were originally found to be liver-resident lymphocytes, the role and importance of ILC2 in liver injury remains poorly understood. In the current study, we sought to determine whether ILC2 is an important regulator of hepatic ischaemia/reperfusion injury (IRI).MethodsILC2-deficient mice (ICOS-T or NSG) and genetically modified ILC2s were used to investigate the role of ILC2s in murine hepatic IRI. Interactions between ILC2s and eosinophils or macrophages were studied in coculture. The role of human ILC2s was assessed in an immunocompromised mouse model of hepatic IRI.ResultsAdministration of IL-33 prevented hepatic IRI in association with reduction of neutrophil infiltration and inflammatory mediators in the liver. IL-33-treated mice had elevated numbers of ILC2s, eosinophils, and regulatory T cells. Eosinophils, but not regulatory T cells, were required for IL-33-mediated hepatoprotection in IRI mice. Depletion of ILC2s substantially abolished the protective effect of IL-33 in hepatic IRI, indicating that ILC2s play critical roles in IL-33-mediated liver protection. Adoptive transfer of ex vivo-expanded ILC2s improved liver function and attenuated histologic damage in mice subjected to IRI. Mechanistic studies combining genetic and adoptive transfer approaches identified a protective role of ILC2s through promoting IL-13-dependent induction of anti-inflammatory macrophages and IL-5-dependent elevation of eosinophils in IRI. Furthermore, in vivo expansion of human ILC2s by IL-33 or transfer of ex vivo-expanded human ILC2s ameliorated hepatic IRI in an immunocompromised mouse model of hepatic IRI.ConclusionsThis study provides insight into the mechanisms of ILC2-mediated liver protection that could serve as therapeutic targets to treat acute liver injury.Impact and implicationsWe report that type 2 innate lymphoid cells (ILC2s) are important regulators in a mouse model of liver ischaemia/reperfusion injury (IRI). Through manipulation of macrophage and eosinophil phenotypes, ILC2s mitigate liver inflammation and injury during liver IRI. We propose that ILC2s have the potential to serve as a therapeutic tool for protecting against acute liver injury and lay the foundation for translation of ILC2 therapy to human liver disease.

Dataset Information

Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury.

Publications

Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury.

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