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Type 1 Innate Lymphoid Cells Are Proinflammatory Effector Cells in Ischemia-Reperfusion Injury of Steatotic Livers

ABSTRACT: Innate lymphoid cells (ILCs), the most recently described family of lymphoid cells, play fundamental roles in tissue homeostasis through the production of key cytokine. Group 1 ILCs, comprised of conventional natural killer cells (cNKs) and type 1 ILCs (ILC1s), have been implicated in regulating immune-mediated inflammatory diseases. However, the role of ILC1s in nonalcoholic fatty liver disease (NAFLD) and ischemia-reperfusion injury (IRI) is unclear. Here, we investigated the role of ILC1 and cNK cells in a high-fat diet (HFD) murine model of partial warm IRI. We demonstrated that hepatic steatosis results in more severe IRI compared to non-steatotic livers. We further elicited that HFD-IRI mice show a significant increase in the ILC1 population, whereas the cNK population was unchanged. Since ILC1 and cNK are major sources of IFN-γ and TNF-α, we measured the level of ex vivo cytokine expression in normal diet (ND)-IRI and HFD-IRI conditions. We found that ILC1s in HFD-IRI mice produce significantly more IFN-γ and TNF-α when compared to ND-IRI. To further assess whether ILC1s are key proinflammatory effector cells in hepatic IRI of fatty livers, we studied both Rag1−/− mice, which possess cNK cells, and a substantial population of ILC1s versus the newly generated Rag1−/−Tbx21−/− double knockout (Rag1-Tbet DKO) mice, which lack type 1 ILCs, under HFD IRI conditions. Importantly, HFD Rag1-Tbet DKO mice showed significant protection from hepatic injury upon IRI when compared to Rag1−/− mice, suggesting that T-bet-expressing ILC1s play a role, at least in part, as proinflammatory effector cells in hepatic IRI under steatotic conditions.

SUBMITTER: Kang J

PROVIDER: S-EPMC9272906 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:Background With the intensification of population aging, the proportion of aging livers in the donor pool is increasing rapidly. Compared with young livers, aging livers are more susceptible to ischemia-reperfusion injury (IRI) during liver transplantation, which greatly affects the utilization rate of aging livers. The potential risk factors associated with IRI in aging livers have not been fully elucidated. Methods In this work, five human liver tissue expression profiling datasets (GSE61260, GSE107037, GSE89632, GSE133815, and GSE151648) and a total of 28 young and aging liver tissues of human (N = 20) and mouse (N = 8) were used to screen and verify the potential risk factors associated with aging livers being more prone to IRI. DrugBank Online was used to screen drugs with potential to alleviate IRI in aging livers. Results The gene expression profile and immune cell composition between young and aging livers had significant differences. Among the differentially expressed genes, aryl hydrocarbon receptor nuclear translocator-like (ARNTL), BTG antiproliferation factor 2 (BTG2), C-X-C motif chemokine ligand 10 (CXCL10), chitinase 3-like 1 (CHI3L1), immediate early response 3 (IER3), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PPARGC1A), mainly involved in the regulation of cell proliferation, metabolism, and inflammation, were also dysregulated in liver tissues suffered from IRI and could form a FOS-centered interaction network. Nadroparin was screened out with the potential to target FOS in DrugBank Online. In addition, the proportion of dendritic cells (DCs) was significantly upregulated in aging livers. Conclusions We combined the expression profiling datasets of liver tissues and samples collected in our hospital for the first time to reveal that the changes in the expression of ARNTL, BTG2, CXCL10, CHI3L1, IER3, FOS, and PPARGC1A and the proportion of dendritic cells may be associated with aging livers being more prone to IRI. Nadroparin may be used to mitigate IRI in aging livers by targeting FOS, and regulation of DC activity may also reduce IRI.

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Type 1 Innate Lymphoid Cells Are Proinflammatory Effector Cells in Ischemia-Reperfusion Injury of Steatotic Livers

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