| First Author | Li Z | Year | 2018 |
| Journal | Cell Death Discov | Volume | 4 |
| Pages | 16 | PubMed ID | 29531813 |
| Mgi Jnum | J:359701 | Mgi Id | MGI:7788933 |
| Doi | 10.1038/s41420-017-0020-7 | Citation | Li Z, et al. (2018) FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation. Cell Death Discov 4:16 |
| abstractText | Alcohol consumption is generally well tolerated by the liver but in some individuals it results in persistent inflammation and liver disease. The mechanisms that regulate alcohol-induced liver inflammation are poorly understood. The transcription factor FOXO3 has previously been shown to be involved in suppressing alcohol-induced liver injury. In this study we demonstrate that in response to alcohol, approximately 10% of mouse hepatic macrophages undergo FOXO3-dependent apoptosis. By 3 days of alcohol exposure total hepatic macrophage numbers declined by 30% but these were restored to normal after 10 days of continued exposure. Whole body or myeloid specific Foxo3(-/-) mice failed to show this apoptotic response. After 10 days of alcohol exposure, Foxo3(-/-) mice had an increased basal inflammatory phenotype and an increase in the proportion of pro-inflammatory CD11b(+), Ly6C(+) infiltrating macrophages (IMs) infiltrating. This led to marked sensitivity to LPS with a 5-fold ALT elevation and liver injury after LPS challenge in Foxo3(-/-) but not WT mice. Restoring the early macrophage apoptosis burst with a pulse of intravenous GdCl(3) at day 2 had no effect on the day 10 phenotype of WT mice but it corrected the hyper-inflammatory phenotype in Foxo3(-/-) mice. In conclusion, FOXO3-dependent hepatic macrophage apoptosis in response to ethanol serves to promote differentiation of infiltrating macrophages thus limiting the magnitude of the inflammatory response to ethanol. |
