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Angiopoietin like protein 4 expression is decreased in activated macrophages
Kenneth R Feingold1, Judy K Shigenaga, Andrew S Cross
1Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121, USA. kenneth.feingold@ucsf.edu
Abstract:
Angiopoietin like protein 4 (ANGPTL4) inhibits lipoprotein lipase (LPL) activity. Previous studies have shown that Toll-like Receptor (TLR) activation increases serum levels of ANGPTL4 and expression of ANGPTL4 in liver, heart, muscle, and adipose tissue in mice. ANGPTL4 is expressed in macrophages and is induced by inflammatory saturated fatty acids. The absence of ANGPTL4 leads to the increased uptake of pro-inflammatory saturated fatty acids by macrophages in the mesentery lymph nodes due to the failure of ANGPTL4 to inhibit LPL activity, resulting in peritonitis, intestinal fibrosis, weight loss, and death. Here we determined the effect of TLR activation on the expression of macrophage ANGPTL4. LPS treatment resulted in a 70% decrease in ANGPTL4 expression in mouse spleen, a tissue enriched in macrophages. In mouse peritoneal macrophages, LPS treatment also markedly decreased ANGPTL4 expression. In RAW cells, a macrophage cell line, LPS, zymosan, poly I:C, and imiquimod all inhibited ANGPTL4 expression. In contrast, neither TNF, IL-1, nor IL-6 altered ANGPTL4 expression. Finally, in cholesterol loaded macrophages, LPS treatment still decreased ANGPTL4 expression. Thus, while in most tissues ANGPTL4 expression is stimulated by inflammatory stimuli, in macrophages TLR activators inhibit ANGPTL4 expression, which could lead to a variety of down-stream effects important in host defense and wound repair.
Insights
Toll-like Receptor (TLR) activation decreases Angiopoietin like protein 4 (ANGPTL4) in macrophages, unlike in other tissues. This inhibition by TLRs impacts macrophage function in host defense and wound repair.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Angiopoietin like protein 4 (ANGPTL4) is an inhibitor of lipoprotein lipase (LPL).
- Toll-like Receptor (TLR) activation typically increases ANGPTL4 expression in various mouse tissues.
- ANGPTL4 is present in macrophages and responds to inflammatory stimuli.
Purpose of the Study:
- To investigate the effect of Toll-like Receptor (TLR) activation on macrophage ANGPTL4 expression.
- To understand the differential regulation of ANGPTL4 by inflammatory stimuli in macrophages versus other tissues.
Main Methods:
- Treatment of mouse spleen and peritoneal macrophages with Lipopolysaccharide (LPS).
- Treatment of RAW macrophage cell line with various TLR agonists (LPS, zymosan, poly I:C, imiquimod).
- Assessment of ANGPTL4 expression levels via quantitative analysis.
Main Results:
- LPS treatment significantly decreased ANGPTL4 expression in mouse spleen and peritoneal macrophages (by 70% in spleen).
- TLR agonists (LPS, zymosan, poly I:C, imiquimod) consistently inhibited ANGPTL4 expression in RAW cells.
- Pro-inflammatory cytokines (TNF, IL-1, IL-6) did not affect ANGPTL4 expression in macrophages.
- LPS also decreased ANGPTL4 expression in cholesterol-loaded macrophages.
Conclusions:
- Contrary to other tissues, TLR activation inhibits ANGPTL4 expression in macrophages.
- This macrophage-specific downregulation of ANGPTL4 by TLRs may have significant implications for host defense and wound repair processes.
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