Natural Killer Cells Contribute to Pathogenesis of Severe Alcoholic Hepatitis by Inducing Lysis of Endothelial Progenitor Cells

Natural Killer Cells Contribute to Pathogenesis of Severe Alcoholic Hepatitis by Inducing Lysis of Endothelial Progenitor Cells.

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Alcoholism: Clinical and Experimental Research
Volume: 44
Number: 1
Page Range: pp. 78-86
Date: 2020
Divisions: Alcoholic Liver Disease
Depositing User: General Admin
Identification Number: 10.1111/acer.14242
ISSN: 0145-6008
Date Deposited: 22 Dec 2020 02:53

Background: Endothelial progenitor cells (EPCs) help in neovascularization and endothelial repair during injury. Patients with cirrhosis show increased number and function of EPCs in circulation.

Methods: Since natural killer (NK) cells regulate EPCs, we investigated the relationship between the 2 in alcoholic cirrhosis (AC, n = 50) and severe alcoholic hepatitis (SAH, n = 18) patients and compared with nonalcoholic cirrhosis (n = 15) and healthy controls (HC, n = 30). Levels of systemic inflammatory cytokines were measured, and coculture assays were performed between EPCs and NK cells in contact-dependent and contact-independent manner. NK cell-mediated killing of EPCs was evaluated, and expression of receptors including fractalkine (FKN) on EPCs and its cognate receptor CX3CR1 on NK cells was studied by RT-PCR assays.

Results: Patients with SAH had higher regulated on activation, normal T cell expressed and secreted (RANTES) (p = 0.01), vascular endothelial growth factor (VEGF) (p = 0.04), IL-1β (p = 0.04), and IL-6 (p = 0.00) growth factors and proinflammatory cytokines as compared to AC and HC. Distinct populations of CD31+ CD34+ EPCs with low and high expression of CD45 were significantly lower in SAH than HC (CD45low , p = 0.03; CD45hi , p = 0.04) and AC (CD45low , p = 0.05; CD45hi , p = 0.02). SAH patients, however, showed increased functional capacity of EPCs including colony formation and LDL uptake. NK cells were reduced in SAH compared with AC (p = 0.002), however with higher granzyme ability (p < 0.001 and p = 0.04, respectively). In SAH, EPC-NK cell interaction assays showed that NK cells lysed the EPCs in both contact-dependent and contact-independent assays. Expression of interaction receptor CX3CR1 was significantly higher on NK cells (p = 0.0005), while its cognate receptor, FKN, was increased on EPCs in SAH patients as compared to HC (p = 0.0055).

Conclusion: We conclude that in SAH, NK cells induce killing of EPCs via CX3CR1/FKN axis that may be one of the key events contributing to disease severity and proinflammatory responses in SAH.

Keywords: CX3CL1; CX3CR1 or FKN (fractalkine); Endothelial Progenitor Cells; NK Cells; Severe Alcoholic Hepatitis.

© 2019 by the Research Society on Alcoholism.

Sehgal, Rashi
Kaur, Savneet
Shasthry, Saggere Murli
Agrawal, Tanvi
Dwivedi, Varsha
Seth, Devanshi
Ramakrishna, Gayatri
Sarin, Shiv Kumar
Trehanpati, Nirupma
Last Modified: 22 Dec 2020 02:53

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