3.1.4. TLR5

Peritoneal injection with the TLR5 ligand flagellin has been shown to induce significant TLR5-mediated liver injury in mice, resulting in IL-6, IL-8, and IL-1β production, coupled with neutrophil and macrophage infiltration into the liver [126]. In the context of NASH, however, hepatocyte TLR5 may possess a protective effect. In mice fed with MCD diet to induce NASH, selective hepatocyte deficiency of TLR5 was shown to exacerbate liver inflammation and fibrosis via elevated expression of TNF-α, monocyte chemoattractant protein (MCP)1, and IL-1β, as well as Timp1, Mmp9, Col1, and collagen deposition [125]. These conflicting results may, however, be the result of hepatocyte versus whole-body knockout of TLR5 and require further study.

#### *Cells* **2019**, *8*, 1324

Unlike hepatocyte-specific TLR5 KO, whole-body KO ameliorates inflammation and fibrogenesis in the CCL4 fibrosis model. TLR5 KO mice demonstrated a significant reduction of inflammatory mediators TNF-α, IL-6, and IL-1β and fibrogenesis, as indicated by downregulation in α-SMA, TGF-β, TIMP1, and collagen deposition compared to WT mice [127]. A significant reduction in NF-κB and MAPK signaling activity was measured in activated HSCs, suggesting a mechanism of hepatic fibrogenesis mediated by the TLR5-activated NF-κB/MAPK signaling pathway in HSCs [127].
