Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis
Background Decompensated 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 res...
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Published in | Frontiers in immunology Vol. 13; p. 828949 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
03.06.2022
|
Subjects | |
Online Access | Get full text |
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Summary: | Background
Decompensated 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.
Methods
A 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.
Results
Frequencies 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.
Conclusion
MDSCs 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ORCID: Nirupma Trehanpati, orcid.org/0000-0002-6109-0033; Shiv K. Sarin, orcid.org/0000-0002-0544-5610 This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology Edited by: Bernahrd Ryffel, Centre National de la Recherche Scientifique (CNRS), France Reviewed by: Sabrin Albeituni, St. Jude Children’s Research Hospital, United States; Pawan Malhotra, International Centre for Genetic Engineering and Biotechnology, India |
ISSN: | 1664-3224 1664-3224 |
DOI: | 10.3389/fimmu.2022.828949 |