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Two-photon fluorescence imaging reveals a Golgi apparatus superoxide anion-mediated hepatic ischaemia-reperfusion signalling pathway.

ABSTRACT: Hepatic ischaemia-reperfusion (IR) injury is mainly attributed to a burst of reactive oxygen species (ROS) that attack biological macromolecules and lead to cell death. The superoxide anion (O₂?^-) is the first ROS to be generated and triggers the production of other ROS; thus, explorations of the role of O₂?^- in the IR process are meaningful. Meanwhile, the Golgi apparatus generates O₂?^- via Golgi-associated proteins, which might play an essential role in IR injury. However, the molecular mechanism by which O₂?^- from the Golgi apparatus regulates hepatic IR injury is unclear. Therefore, to solve this problem, a two-photon (TP) excited fluorescence probe (CCA) was designed and prepared for the reversible detection of O₂?^- in the Golgi apparatus. With the assistance of TP fluorescence microscopy, we observed a substantial increase in the levels of O₂?^- in the Golgi apparatus of an IR mouse liver for the first time, as well as increased caspase-2 activity and apoptosis. Furthermore, we found that the tumour necrosis factor (TNF-?) functions as a positive mediator of O₂?^- generation. Based on these data, we identified the potential signalling pathway in the Golgi that mediates O₂?^- fluctuations in IR mice and revealed the related molecular mechanisms; we also provide a new target for treating IR injury.

SUBMITTER: Zhang W

PROVIDER: S-EPMC6346286 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Two-photon fluorescence imaging reveals a Golgi apparatus superoxide anion-mediated hepatic ischaemia-reperfusion signalling pathway.

Zhang Wen W Zhang Jiao J Li Ping P Liu Jihong J Su Di D Tang Bo B

Chemical science 20181106 3

Hepatic ischaemia-reperfusion (IR) injury is mainly attributed to a burst of reactive oxygen species (ROS) that attack biological macromolecules and lead to cell death. The superoxide anion (O2˙-) is the first ROS to be generated and triggers the production of other ROS; thus, explorations of the role of O2˙- in the IR process are meaningful. Meanwhile, the Golgi apparatus generates O2˙- via Golgi-associated proteins, which ...[more]

PMID: 30774882

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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

Two-photon fluorescence imaging reveals a Golgi apparatus superoxide anion-mediated hepatic ischaemia-reperfusion signalling pathway.

Publications

Two-photon fluorescence imaging reveals a Golgi apparatus superoxide anion-mediated hepatic ischaemia-reperfusion signalling pathway.

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