Role of TLR9 in hepatic stellate cells and experimental liver fibrosis.
Accumulating evidence indicates that bacteria and bacterial products promote hepatic fibrogenesis. The activation of hepatic stellate cells (HSC) plays a central role in hepatic fibrosis. Here, we demonstrate that HSC express toll-like receptor 9 (TLR9), a pattern recognition receptor that is activated by CpG motifs present specifically in bacterial DNA. Upon CpG stimulation human as well as murine HSC isolated from wild-type (TLR9+/+) mice express increased levels of the profibrogenic chemokine monocyte chemotactic protein 1 (MCP-1). In contrast, HSC isolated from TLR9 deficient (TLR9-/-) mice lacked CpG motif induced MCP-1 expression indicating the functionality of TLR9 in HSC. Bile duct ligation revealed significantly lower hepatic MCP-1 and collagen expression and less hepatic fibrosis in TLR9-/- compared to TLR9+/+ mice. In addition, the expression of hepatic alpha-smooth-muscle actin, a known marker for HSC activation, was reduced in TLR9-/- mice indicating that bacterial DNA induces the activation of HSC and therefore promotes hepatic fibrosis.
Gäbele
Erwin
E
Department of Internal Medicine I, University of Regensburg, Franz-Josef-Strauss-Alle 11, D-93042 Regensburg, Germany.
Mühlbauer
Marcus
M
Dorn
Christoph
C
Weiss
Thomas S
TS
Froh
Matthias
M
Schnabl
Bernd
B
Wiest
Reiner
R
Schölmerich
Jürgen
J
Obermeier
Florian
F
Hellerbrand
Claus
C