Accumulation of myeloid lineage cells is mapping out liver fibrosis post injury: a targetable lesion using Ketanserin

摘要

Liver fibrosis is problematic after persistent injury. However, little is known about its response to an acute insult. Accumulation of myeloid lineage cells contributes into the promotion and resolution of inflammation and fibrosis. Using Cre-transgenic mice that specifically mark myeloid lineage cells with EYFP and burn as a model of acute systemic injury, we investigated the role of myeloid lineage cells in the liver after acute injury. Our data show that thermal injury in mice (30% total body surface area) induces fibrosis predominantly around portal venules whereas myeloid cells are enriched throughout the liver. The fibrosis peaks around 1–2 weeks post injury and resolves by week 3. Ablating myeloid cells led to lower fibrosis. Through FACS sorting, we isolated myeloid lineage cells (EYFP +ve cells) from injured animals and from the control uninjured animals and subjected the extracted RNA from these cells to microarray analysis. Microarray analysis revealed an inflammatory signature for EYFP +ve cells isolated from injured animals in comparison with control cells. Moreover, it showed modulation of components of the serotonin (5-HT) pathway in myeloid cells. Antagonizing the 5HT_(2A/2C)receptor decreased fibrosis in thermally injured mice by skewing macrophages away from their pro-fibrotic phenotype. Macrophages conditioned with Ketanserin showed a lower pro-fibrotic phenotype in a co-culture system with mesenchymal cells. There is a spatiotemporal pattern in liver fibrosis post-thermal injury, which is associated with the influx of myeloid cells. Treating mice with a 5HT_(2A/2C)receptor antagonist promotes an anti-fibrotic effect, through modulating the phenotype of macrophages. Liver damage: Injury-induced fibrosis A drug that affects serotonin pathway in the liver following systemic injury could help limit damage caused by fibrosis. Severe burn injuries can result in liver fibrosis, the over-production of connective tissues promoted by pro-inflammatory immune cells, including those derived from bone marrow myeloid cells. Chronic fibrosis can cause tissue dysfunction and extensive scarring which can contribute into liver dysfunction. In experiments on mice, Saeid Amini-Nik and Marc Jeschke at the University of Toronto, Canada, and co-workers demonstrated that myeloid cells are enriched in the liver after thermal injury, with a phenotype reminiscent of inflammatory macrophages. Treating the mice with a drug called Ketanserin, which targets serotonin pathway, altered the myeloid-derived immune cells so that they were less likely to cause fibrosis. This suggests a possible therapy for liver fibrosis post-injury.