Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State

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.

Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness

“…However, unlike DTT, pre-treatment with Tn prevents LPS-mediated M1-like stimulation of RAW 264.7 mouse macrophage cells (Figure 1B and 1C ) and prevented macrophage-mediated endocytosis of breast cancer cells (Figure 1D ). Previous reports showed that DTT and ER chaperones stabilize paraoxonase 2 (PON2) that may promote a more M2-like phenotype in atherosclerosis [ 26 , 27 ], which was not observed in the current study. Whether these differential effects on macrophage plasticity observed by chemical inducers of UPR are due to the differing potency of UPR stimulation (Figure 1A ), the possible requirement of glycosylated protein biosynthesis for macrophage stimulation [ 28 ] or the highly reductive basal redox state existing in macrophages that may curtail DTT efficacy are still unclear [ 29 ].…”

Cholesterol reduction and macrophage function: role of paraoxonases

“…Transfection of human PON2 into macrophages from PON2 −/− mice inhibited the induction of a pro-inflammatory M1 phenotype and promoted M2 phenotypic differentiation. These data suggest that PON2 inhibits the differentiation of monocytes to a pro-inflammatory phenotype and can act as a switch from an M1 to an M2 phenotype in macrophages (44). …”

“…PON2 also regulates macrophage differentiation (44). MPMs isolated from PON2 −/− mice display a pro-inflammatory phenotype (increased TNFα, IL-6 and arginase II) compared to wild-type mice (44).…”

“…MPMs isolated from PON2 −/− mice display a pro-inflammatory phenotype (increased TNFα, IL-6 and arginase II) compared to wild-type mice (44). Further, the expression of IL-10 and arginase I, markers of anti-inflammatory M2 macrophages, was significantly reduced in MPMs of PON2 −/− mice compared to controls.…”

“…Further, the expression of IL-10 and arginase I, markers of anti-inflammatory M2 macrophages, was significantly reduced in MPMs of PON2 −/− mice compared to controls. IL-4, an activator of M2 macrophage differentiation, did not alter the pro-inflammatory phenotype of MPMs from PON2 −/− mice (44). These cells were characterized by enhanced phagocytic activity and oxidant formation.…”