Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation via Hsp90
A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment of inflammatory monocytes/macrophages (Mo/MØ). These key cellular events of ALD pathogenesis may be mediated by extracellular vesicles (EVs). EVs transfer biomaterials, including proteins and miRNAs, a...
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Published in | Hepatology (Baltimore, Md.) Vol. 67; no. 5; pp. 1986 - 2000 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
06.04.2018
|
Online Access | Get full text |
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Summary: | A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC)
activation and recruitment of inflammatory monocytes/macrophages
(Mo/MØ). These key cellular events of ALD pathogenesis may be mediated
by extracellular vesicles (EVs). EVs transfer biomaterials, including proteins
and miRNAs, and have recently emerged as important effectors of intercellular
communication. We hypothesized that circulating EVs from mice with ALD have a
protein cargo characteristic of the disease and mediate biological effects by
activating immune cells. The total number of circulating EVs was increased in
mice with ALD (ALD-EV) compared to pair-fed controls (control-EV). Mass
spectrometry analysis of circulating EVs revealed a distinct signature for
proteins involved in inflammatory responses, cellular development and cellular
movement between ALD-EVs and control-EVs. We also identified uniquely important
proteins in ALD-EVs that were not present in control-EVs. When ALD-EVs were
injected intravenously into alcohol-naïve mice, we found evidence of
uptake of ALD-EVs in recipient livers in hepatocytes and MØs.
Hepatocytes isolated from mice after transfer of ALD-EVs, but not control-EVs,
showed increased MCP-1 mRNA and protein expression suggesting a biological
effect of ALD-EVs. Compared to control-EV recipient mice, ALD-EV recipient mice
had increased numbers of F4/80
hi
CD11b
lo
KCs and increased
percentages of TNFα
+
IL-12/23
+
(inflammatory/M1) KCs and infiltrating monocytes
(F4/80
int
CD11b
hi
) while the percentage of
CD206
+
CD163
+
(anti-inflammatory/M2)
KCs was decreased.
In vitro
, ALD-EVs increased TNFα and
IL-1β production in MØ and reduced CD163 and CD206 expression.
We identified Heat shock protein 90 (Hsp90) in ALD-EVs as the mediator of
ALD-EV-induced MØ activation. |
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ISSN: | 0270-9139 1527-3350 |
DOI: | 10.1002/hep.29732 |