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Two-photon Intravital Imaging of Leukocytes During the Immune Response in Lipopolysaccharide-treated Mouse Liver
Published on: February 6, 2018
Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia
Debra L Laskin1, Li Chen, Pamela A Hankey
1Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Rd., Piscataway, NJ 08854, USA. laskin@eohsi.rutgers.edu
Abstract:
Acute endotoxemia is associated with excessive production of proinflammatory mediators by hepatic macrophages and endothelial cells, which have been implicated in liver injury and sepsis. In these studies, we analyzed the role of MSP and its receptor STK in regulating the activity of these cells. Acute endotoxemia, induced by administration of LPS (3 mg/kg) to mice, resulted in increased expression of STK mRNA and protein in liver macrophages and endothelial cells, an effect that was dependent on TLR-4. This was correlated with decreased MSP and increased pro-MSP in serum. In Kupffer cells, but not endothelial cells, MSP suppressed LPS-induced NOS-2 expression, with no effect on COX-2. LPS treatment of mice caused a rapid (within 3 h) increase in the proinflammatory proteins NOS-2, IL-1beta, and TNF-alpha, as well as TREM-1 and TREM-3 and the anti-inflammatory cytokine IL-10 in liver macrophages and endothelial cells. Whereas LPS-induced expression of proinflammatory proteins was unchanged in STK-/- mice, IL-10 expression was reduced significantly. Enzymes mediating eicosanoid biosynthesis including COX-2 and mPGES-1 also increased in macrophages and endothelial cells after LPS administration. In STK-/- mice treated with LPS, mPGES-1 expression increased, although COX-2 expression was reduced. LPS-induced up-regulation of SOD was also reduced in STK-/- mice in liver macrophages and endothelial cells. These data suggest that MSP/STK signaling plays a role in up-regulating macrophage and endothelial cell anti-inflammatory activity during hepatic inflammatory responses. This may be important in protecting the liver from tissue injury.
Insights
The study found that MSP/STK signaling helps liver cells reduce inflammation during endotoxemia. This pathway may protect the liver from injury by regulating macrophage and endothelial cell activity.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Acute endotoxemia triggers excessive pro-inflammatory mediator production by hepatic macrophages and endothelial cells, contributing to liver injury and sepsis.
- The role of Macrophage-Specific Protein (MSP) and its receptor Tyrosine Kinase (STK) in regulating these cellular responses during endotoxemia remains unclear.
Purpose of the Study:
- To investigate the role of MSP/STK signaling in modulating hepatic macrophage and endothelial cell activity during acute endotoxemia.
- To determine the impact of MSP/STK signaling on the expression of key inflammatory and anti-inflammatory mediators in the liver.
Main Methods:
- Induction of acute endotoxemia in mice using lipopolysaccharide (LPS).
- Analysis of STK expression in liver macrophages and endothelial cells, and its correlation with serum MSP levels.
- Assessment of inflammatory (NOS-2, IL-1beta, TNF-alpha, TREM-1, TREM-3, COX-2, mPGES-1) and anti-inflammatory (IL-10, SOD) mediator expression in wild-type and STK-/- mice.
Main Results:
- LPS administration increased STK expression in liver macrophages and endothelial cells, dependent on Toll-like receptor 4 (TLR-4).
- MSP suppressed LPS-induced NOS-2 expression in Kupffer cells, while STK deficiency led to reduced IL-10 expression and altered COX-2 and mPGES-1 levels.
- LPS-induced pro-inflammatory responses were generally not altered in STK-/- mice, but the up-regulation of anti-inflammatory cytokine IL-10 and SOD was significantly reduced.
Conclusions:
- MSP/STK signaling plays a crucial role in up-regulating anti-inflammatory activity in hepatic macrophages and endothelial cells during endotoxemia.
- This signaling pathway may be vital for protecting the liver against tissue injury associated with inflammatory responses.
