Interference with Macrophage Differentiation and Activation
Monocytes that have entered the arterial intima subsequently differentiate into resident macrophages of at least two major subtypes that differentially produce a variety of proand anti-inﬂammatory mediators. In the subendothelial space, the macrophages become activated and comprise key targets for the anti-inﬂammatory action of HDLs. Incubation with HDLs primed isolated murine bone marrow macrophages into alternative M2 macrophages with anti-inﬂammatory features (Sanson et al. 2013). Moreover, HDLs were potent inhibitors of interferongamma-mediated expression of pro-inﬂammatory M1 markers in isolated mouse macrophages, and, interestingly, experiments performed with macrophages from STAT6-deﬁcient mice demonstrated that STAT6 plays an essential role in the HDL-mediated shift of the macrophage phenotype to M2 (Sanson et al. 2013). However, other investigators could not replicate these observations, when using primary human monocyte-derived macrophages (Colin et al. 2014). A recent study provided novel mechanistic insights into the anti-inﬂammatory effects of HDLs in macrophages. Thus, administration of native HDL, rHDL, or apoA-I to mice challenged with a toll-like receptor (TLR) agonist protected from liver damage and reduced serum levels of pro-inﬂammatory cytokines, which was supposed to be due the ability of HDLs to reduce cytokine production in activated macrophages (De Nardo et al. 2014). The anti-inﬂammatory action of HDL particles on macrophages was explained by their ability to induce the expression of activating transcription factor 3 (ATF3), which functions as a repressor of pro-inﬂammatory target genes (De Nardo et al. 2014).
During the past decades, a considerable amount of data has been published revealing that natural regulatory T cells, which dampen inﬂammatory responses, may help decrease the atherosclerotic disease burden. The ﬁndings of a recent murine study imply that apoA-I could promote the expansion of regulatory T cells. Subcutaneous injection of human lipid-free apoA-I in LDL receptor/apoA-I double knockout mice fed an atherogenic diet restored the regulatory T-cell population in the lymph nodes (Wilhelm et al. 2010). In these animals the raise in the number of regulatory T cells in the lymph nodes was accompanied by a reversal of the inﬂammatory and autoimmune phenotype.