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Published on: November 28, 2015
Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State
Marie Koren-Gluzer1, Mira Rosenblat1, Tony Hayek2
1The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Health Care Campus, 31096 Haifa, Israel.
Abstract:
Inflammatory processes are involved in atherosclerosis development. Macrophages play a major role in the early atherogenesis, and they are present in the atherosclerotic lesion in two phenotypes: proinflammatory (M1) or anti-inflammatory (M2). Paraoxonase 2 (PON2) is expressed in macrophages, and it was shown to protect against atherosclerosis. Thus, the aim of our study was to analyze the direct effect of PON2 on macrophage inflammatory phenotypes. Ex vivo studies were performed with murine peritoneal macrophages (MPM) harvested from control C57BL/6 and PON2-deficient (PON2KO) mice. PON2KO MPM showed an enhanced proinflammatory phenotype compared to the control, both in the basal state and following M1 activation by IFNγ and lipopolysaccharide (LPS). In parallel, PON2KO MPM also showed reduced anti-inflammatory responses in the basal state and also following M2 activation by IL-4. Moreover, the PON2-null MPM demonstrated enhanced phagocytosis and reactive oxygen species (ROS) production in the basal state and following M1 activation. The direct effect of PON2 was shown by transfecting human PON2 (hPON2) into PON2KO MPM. PON2 transfection attenuated the macrophages' response to M1 activation and enhanced M2 response. These PON2 effects were associated with attenuation of macrophages' abilities to phagocyte and to generate ROS. We conclude that PON2 promotes an M1 to M2 switch in macrophage phenotypes.
Insights
Paraoxonase 2 (PON2) influences macrophage inflammatory responses. Studies show PON2 promotes a shift from proinflammatory (M1) to anti-inflammatory (M2) macrophage phenotypes, impacting atherosclerosis development.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Biology
Background:
- Inflammation is central to atherosclerosis development.
- Macrophages, with proinflammatory (M1) and anti-inflammatory (M2) phenotypes, are key players in atherogenesis.
- Paraoxonase 2 (PON2) expression in macrophages is protective against atherosclerosis.
Purpose of the Study:
- To investigate the direct impact of PON2 on macrophage inflammatory phenotypes.
- To understand PON2's role in regulating M1 and M2 macrophage polarization.
Main Methods:
- Ex vivo studies using murine peritoneal macrophages (MPM) from control and PON2-deficient (PON2KO) mice.
- Macrophage activation using IFNγ, lipopolysaccharide (LPS), and IL-4.
- Transfection of human PON2 (hPON2) into PON2KO MPM to assess direct effects.
- Analysis of phagocytosis and reactive oxygen species (ROS) production.
Main Results:
- PON2KO MPM exhibited an enhanced proinflammatory (M1) phenotype and reduced anti-inflammatory (M2) responses.
- PON2-null macrophages showed increased phagocytosis and ROS production.
- hPON2 transfection into PON2KO MPM attenuated M1 activation, enhanced M2 response, and reduced phagocytosis and ROS generation.
Conclusions:
- PON2 directly influences macrophage polarization.
- PON2 promotes a switch from M1 to M2 macrophage phenotypes.
- These findings highlight PON2's atheroprotective role by modulating macrophage inflammatory status.
