Background
Chronic hepatic inflammation leads to liver fibrosis, which may progress to cirrhosis, a condition with high morbidity. Our aim was to assess the as yet unknown role of innate immunity protein CD5L in liver fibrosis.
Methods
CD5L was measured by ELISA in plasma samples from cirrhotic (
n
= 63) and hepatitis (
n
= 39) patients, and healthy controls (
n
= 7), by immunohistochemistry in cirrhotic tissue (
n
= 12), and by quantitative RT-PCR in mouse liver cell subsets isolated by cell sorting. Recombinant CD5L (rCD5L) was administered into a murine model of CCl
4
-induced fibrosis, and damage, fibrosis and hepatic immune cell infiltration, including the LyC6
hi
(pro-fibrotic)-LyC6
low
(pro-resolutive) monocyte ratio were determined. Moreover, rCD5L was added into primary human hepatic stellate cells to study transforming growth factor β (TGFβ) activation responses.
Findings
Cirrhotic patients showed elevated plasma CD5L concentrations as compared to patients with hepatitis and healthy controls (Mann-Whitney test
p
< 0·0001). Moreover, plasma CD5L correlated with disease progression, FIB4 fibrosis score (r:0·25,
p
< 0·0001) and tissue expression (
r
= 0·649;
p
= 0·022). Accordingly, CCl
4
-induced damage increased CD5L levels in total liver, particularly in hepatocytes and macrophages. rCD5L administration attenuated CCl
4
-induced injury and fibrosis as determined by reduced serum transaminase and collagen content. Moreover, rCD5L inhibited immune cell infiltration and promoted a phenotypic shift in monocytes from LyC6
hi
to LyC6
low
. Interestingly, rCD5L also had a direct effect on primary human hepatic stellate cells promoting SMAD7 expression, thus repressing TGFβ signalling.
Interpretation
Our study identifies CD5L as a key pleiotropic inhibitor of chronic liver injury.
Fund
Fundació Marató TV3, AGAUR and the ISCIII-EDRF.
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