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Updated: Mar 21, 2026
Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen
Published on: November 27, 2019
The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury
Mili Mandal1, Carol R Gardner1, Richard Sun1
1Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
Abstract:
Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs.
Insights
The spleen is a source of macrophages involved in acetaminophen-induced liver injury. Splenectomy alters macrophage populations and inflammatory responses in the liver following acetaminophen exposure.
Area of Science:
- Immunology
- Hepatology
- Cell Biology
Background:
- Macrophages play a dual role in acetaminophen (APAP)-induced liver injury, mediating both pro- and anti-inflammatory responses.
- The spleen's contribution as an extramedullary source of hepatic macrophages in APAP toxicity is not fully understood.
Purpose of the Study:
- To investigate the spleen as a source of macrophages contributing to APAP-induced hepatotoxicity.
- To analyze the impact of splenectomy on macrophage populations and inflammatory markers in the liver following APAP administration.
Main Methods:
- Mice were administered APAP (300mg/kg, i.p.) and analyzed for immune cell infiltration in the spleen and liver.
- Flow cytometry was used to characterize macrophage subpopulations (Ly6G, Ly6C, F4/80) and myeloid-derived suppressor cells (MDSCs).
- Expression of chemokine receptors (CCR2, CX3CR1) and inflammatory markers (galectin-3, TNF-α, FIZZ-1, YM-1) were assessed in the liver.
Main Results:
- APAP administration increased granulocytic (Ly6G+) and monocytic (Ly6G-) cells in spleen and liver, with Ly6G+ cells exhibiting an MDSC phenotype.
- Splenectomy led to increased pro-inflammatory (Ly6C(hi)) and anti-inflammatory (Ly6C(lo)) macrophages in the liver post-APAP.
- Splenectomy altered the expression of chemokine receptors and blunted APAP-induced increases in pro-inflammatory galectin-3+ macrophages and TNF-α, while affecting anti-inflammatory markers.
Conclusions:
- Multiple macrophage subpopulations with distinct pro- and anti-inflammatory functions respond to APAP-induced liver injury.
- The spleen serves as a significant extramedullary reservoir for hepatic macrophages, influencing the inflammatory milieu during APAP toxicity.
- Targeting splenic macrophage populations may offer therapeutic strategies for mitigating APAP-induced hepatotoxicity.
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