Granulocytic myeloid‐derived suppressor cell population increases with the severity of alcoholic liver disease

Gao, Miaomiao; Huang, Ang; Sun, Zijian; Sun, Ying; Chang, Binxia; Zhang, Jiyuan; Zou, Zhengsheng

doi:10.1111/jcmm.14109

Cited by 14 publications

(9 citation statements)

References 39 publications

(86 reference statements)

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“…It was earlier reported that M-MDSCs suppressed T-cell functions and antimicrobialspecific innate immune responses in ACLF patients (26). An increase in peripheral and intrahepatic G-MDSC populations was reported in ALC (Alcoholic liver cirrhosis) patients (27). In our study, we also found a significant increase in MDSCs, especially G-MDSCs, in cirrhosis patients with sepsis.…”

Section: Discussionsupporting

confidence: 81%

Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis

et al. 2022

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BackgroundDecompensated cirrhosis patients are more prone to bacterial infections. Myeloid-derived suppressor cells (MDSCs) expand in sepsis patients and disrupt immune cell functions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy helps in restoring immune cell functions and resolving infections. Its role in MDSC modulation in cirrhosis with sepsis is not well understood.MethodsA total of 164 decompensated cirrhotic—62 without (w/o), 72 with sepsis, and 30 with sepsis treated with GM-CSF—and 15 healthy were studied. High-dimensional flow cytometry was performed to analyze MDSCs, monocytes, neutrophils, CD4 T cells, and Tregs at admission and on days 3 and day 7. Ex vivo co-cultured MDSCs with T cells were assessed for proliferation and apoptosis of T cells and differentiation to Tregs. Plasma factors and mRNA levels were analyzed by cytokine-bead assay and qRT-PCR.ResultsFrequencies of MDSCs and Tregs were significantly increased (p = 0.011 and p = 0.02) with decreased CD4 T cells (p = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) (p = 0.000, p = 0.07, and p = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels (p = 0.016, p = 0.043, and p = 0.045). Ex vivo co-cultured MDSCs with T cells drove T-cell apoptosis (p = 0.03, p = 0.03) with decreased T-cell proliferation and enhanced FOXP3+ expression (p = 0.044 and p = 0.043) in sepsis compared to w/o sepsis at day 0. Moreover, blocking the MDSCs with inhibitors suppressed FOXP3 expression. GM-CSF treatment in sepsis patients significantly decreased MDSCs and FOXP3+ Tregs but increased CD4 T-cell functionality and improved survival.ConclusionMDSCs have an immunosuppressive function by expanding FOXP3+ Tregs and inhibiting CD4+ T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.

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Section: Discussionsupporting

confidence: 81%

Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis

et al. 2022

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“…Accumulating evidence indicates that gMDSC play an important role in the development of microbial infections, autoimmune disorders, and cancer. The gMDSC population is elevated in patients with alcoholic liver disease and closely associated with disease progression ( 9 ). However, we know little regarding whether gMDSC have impaired antimicrobial response or phagocytic capacity in patients with HBV-ACLF.…”

Section: Introductionmentioning

confidence: 99%

Granulocytic myeloid-derived suppressor cells increase infection risk via the IDO/IL-10 pathway in patients with hepatitis B virus-related liver failure

Sun²,

Yang³

et al. 2023

Front. Immunol.

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Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) results in high susceptibility to infection. Although granulocytic myeloid-derived suppressor cells (gMDSC) are elevated in patients with HBV-ACLF, their role in HBV-ACLF pathogenesis is unknown. To elucidate the mechanism of gMDSC expansion and susceptibility to infection in HBV-ACLF patients, we analyzed the proportion of gMDSC in the peripheral blood and organ tissues of patients with HBV-ACLF and an ACLF mouse model established by continuous injection (eight times) of Concanavalin by flow cytometry and immunohistochemistry. We found that the proportion of gMDSC increased significantly in the blood and liver of patients with HBV-ACLF. This increase was positively correlated with disease severity, prognosis, and infection. gMDSC percentages were higher in peripheral blood, liver, spleen, and bone marrow than control levels in the ACLF mouse model. Immunofluorescence revealed that the gMDSC count increased in the liver of patients with HBV-ACLF as well as in the liver and spleen of ACLF mice. We further exposed peripheral blood monocyte cells from healthy donors to plasma from HBV-ACLF patients, recombinant cytokines, or their inhibitor, and found that TNF-α led to gMDSC expansion and significant upregulation of indoleamine 2, 3-dioxygenase (IDO), while blocking TNF-α signaling decreased gMDSC. Moreover, we detected proliferation and cytokine secretion of T lymphocytes when purified gMDSC was co-cultured with Pan T cells or IDO inhibitor and found that TNF-α-induced gMDSC inhibited T cell proliferation and interferon-γ production through the IDO signaling pathway. Lastly, the ability of gMDSC to phagocytose bacteria was low in patients with HBV-ACLF. Our findings elucidate HBV-ACLF pathogenesis and provide potential therapeutic targets.

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“…The correlation between MDSCs and coagulation indexes has also been reported in other diseases. In alcoholic liver cirrhosis patients, level of plasma ARG-1 secreted by MDSCs were correlated with INR ( 33 ). In adult acute myeloid leukemia patients, MDSCs were significantly increased, and the level of MDSCs was correlated well with plasma D-dimer levels ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Continuous renal replacement therapy attenuates polymorphonuclear myeloid-derived suppressor cell expansion in pediatric severe sepsis

et al. 2022

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BackgroundMyeloid-derived suppressor cells (MDSCs) expansion is an important mechanism underlying immunosuppression during sepsis. Though continuous renal replacement therapy (CRRT) may attenuate hyperinflammatory response in sepsis, its role in regulating MDSCs is unknown. The aim of this study was to assess the potential role of CRRT involved in sepsis-induced MDSCs expansion in pediatric sepsis.MethodThe proportion of polymorphonuclear MDSCs (PMN-MDSCs) was detected before CRRT (pre-CRRT), at 24 hours after CRRT (CRRT 1st day) and on the 7th day after CRRT (CRRT 7th day). The correlation analyses were performed to elucidate the relationship of MDSCs with clinical indexes in sepsis.ResultsTotally 22 pediatric patients with sepsis were enrolled [median age 44 (IQR15, 83) months]. PMN-MDSCs were expanded in pediatric sepsis compared with healthy controls (4.30% vs. 0.37%, P=0.04). The proportion of PMN-MDSCs showed a decreased tendency on the CRRT 7th day compared with that on the CRRT 1st day in survivors (2.29% vs.5.32%, P = 0.088). There was no significant difference in the proportion of PMN-MDSCs between survivors and non-survivors before CRRT (4.51% vs. 3.33%, P=0.745). The levels of interleukin 6 (IL-6) was decreased on the CRRT 7th day compared with CRRT 1st day in survivors. In the subgroups of patients with significantly decreased IL-6 levels after CRRT, the proportion of PMN-MDSCs on the CRRT 7th day were also significantly decreased compared with that on the CRRT 1st day (2.21% vs. 6.67%, P = 0.033).ConclusionThe proportion of PMN-MDSCs was down-regulated on the CRRT 7th day in survivors with sepsis. The reduced PMN-MDSCs expansion may relate to decreased IL-6 level.

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Granulocytic myeloid‐derived suppressor cell population increases with the severity of alcoholic liver disease

Cited by 14 publications

References 39 publications

Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis

Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis

Granulocytic myeloid-derived suppressor cells increase infection risk via the IDO/IL-10 pathway in patients with hepatitis B virus-related liver failure

Continuous renal replacement therapy attenuates polymorphonuclear myeloid-derived suppressor cell expansion in pediatric severe sepsis

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