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

Abstract

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 5HT2A/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 5HT2A/2C receptor antagonist promotes an anti-fibrotic effect, through modulating the phenotype of macrophages.

Microbiota transfer following liver surgery involves microbial extracellular vesicle migration that affects liver immunity

“… 25 This mechanism is mediated by adhesion molecules, chemoattractants, and cytokines. 26 The postoperative immunomodulatory effect of administrating pbMVs was compared with vehicle (saline-treated group) after a sham laparotomy surgery on POD4 (scheme 3). They were administered intragastrically twice on POD1 and daily for 3 days until POD4, while the control group received the vehicle alone.…”

5-HT1A Receptor Function Makes Wound Healing a Happier Process

“…The regenerative role of serotonin has already been well-established in the liver (Lesurtel et al, 2006; Amini-Nik et al, 2018). The 5-HT1A receptor specifically has been identified as a key modulator in several other tissues, such as within the spinal motor neuron regeneration process in zebrafish (Barreiro-Iglesias et al, 2015).…”

“…Nevertheless, this interplay has been documented in both directions where macrophages can enhance fibroblast migration (Dewor et al, 2007; Amini-Nik et al, 2014; Amini-Nik et al, 2018) as well. In normal tissue, the 5-HT1A receptor is also expressed in platelets, neutrophils, macrophages, and mast cells, all of which are components of the wound microenvironment (Shah and Amini-Nik, 2017).…”

The janus face of serotonin: Regenerative promoter and chronic liver disease aggravator

“…It seems that 5-HTR 2B is more specifically targeted towards HSCs in the liver, while 5-HTR 2A, 2C, and 7 seem more closely associated with inflammation and oxidative stress damage in liver fibrosis. Saeid et al treated thermal-injured mice with a 5HTR 2A/2C antagonist (Ketanserin) and found that it could promote anti-fibrotic effects by regulating the phenotype of macrophages [ 77 ]. A study by Atallah et al showed that blocking 5-HTR 2A with Ketanserin or 5-HTR 7 with SB-269970 reduced oxidative stress/TGF-β1-induced liver fibrosis in CCl4-challenged rats [ 78 ], which were consistent with those reported by Dalia et al [ 79 ].…”