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2015 ; 11
(8
): 1280-92
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Macrophage autophagy protects against liver fibrosis in mice
#MMPMID26061908
Lodder J
; Denaës T
; Chobert MN
; Wan J
; El-Benna J
; Pawlotsky JM
; Lotersztajn S
; Teixeira-Clerc F
Autophagy
2015[]; 11
(8
): 1280-92
PMID26061908
show ga
Autophagy is a lysosomal degradation pathway of cellular components that displays
antiinflammatory properties in macrophages. Macrophages are critically involved
in chronic liver injury by releasing mediators that promote hepatocyte apoptosis,
contribute to inflammatory cell recruitment and activation of hepatic fibrogenic
cells. Here, we investigated whether macrophage autophagy may protect against
chronic liver injury. Experiments were performed in mice with mutations in the
autophagy gene Atg5 in the myeloid lineage (Atg5(fl/fl) LysM-Cre mice, referred
to as atg5(-/-)) and their wild-type (Atg5(fl/fl), referred to as WT)
littermates. Liver fibrosis was induced by repeated intraperitoneal injection of
carbon tetrachloride. In vitro studies were performed in cultures or co-cultures
of peritoneal macrophages with hepatic myofibroblasts. As compared to WT
littermates, atg5(-/-) mice exposed to chronic carbon tetrachloride
administration displayed higher hepatic levels of IL1A and IL1B and enhanced
inflammatory cell recruitment associated with exacerbated liver injury. In
addition, atg5(-/-) mice were more susceptible to liver fibrosis, as shown by
enhanced matrix and fibrogenic cell accumulation. Macrophages from atg5(-/-) mice
secreted higher levels of reactive oxygen species (ROS)-induced IL1A and IL1B.
Moreover, hepatic myofibroblasts exposed to the conditioned medium of macrophages
from atg5(-/-) mice showed increased profibrogenic gene expression; this effect
was blunted when neutralizing IL1A and IL1B in the conditioned medium of
atg5(-/-) macrophages. Finally, administration of recombinant IL1RN (interleukin
1 receptor antagonist) to carbon tetrachloride-exposed atg5(-/-) mice blunted
liver injury and fibrosis, identifying IL1A/B as central mediators in the
deleterious effects of macrophage autophagy invalidation. These results uncover
macrophage autophagy as a novel antiinflammatory pathway regulating liver
fibrosis.
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