| First Author | Takimoto Y | Year | 2023 |
| Journal | iScience | Volume | 26 |
| Issue | 3 | Pages | 106220 |
| PubMed ID | 36876136 | Mgi Jnum | J:334982 |
| Mgi Id | MGI:7443806 | Doi | 10.1016/j.isci.2023.106220 |
| Citation | Takimoto Y, et al. (2023) Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience 26(3):106220 |
| abstractText | The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b(+) cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy. |
