High dietary salt (NaCl) is a major risk factor for cardiovascular disease (CVD). We have shown that macrophages play a key role in the regulation of interstitial tonicity and that NaCl-induced hypertonicity amplifies T cell (Th17) polarization. We therefore hypothesize that NaCl-induced hypertonicity also affects macrophage polarization. Here we have investigated the effect of NaCl-induced hypertonicity on the IL4/IL13-induced alternative activation of M2 macrophages (AAM). Bone marrow cells from C57BL/6 mice were differentiated in the presence of M-CSF for 7 days to generate M0 macrophages. To induce AAM, M0 macrophages were then incubated with IL4/IL13 for 24h in the presence of 0-40mM NaCl. Quantitative RT-PCR was used to analyze AAM signature genes (e.g. Mrc1, Arg1, Fizz1, Ym-1, PD-L2). NaCl specifically blunted the upregulation of these genes and Klf4 and Irf4 (two transcription factors essential for AAM polarization). In contrast, osmotic stress by mannitol or urea did not have an effect. In previous experiments Sgk1 played a pivotal role in Th17 polarization. In contrast, Sgk1 was not involved in the NaCl-effect on AAM macrophages. It has been shown that histone modifications are essential for AAM. In RAW264.3 macrophages, IL4/IL13 induced an increase in H3K4 trimethylation of a number of genes, including Mrc1. However this H3K4 trimethylation was blunted by NaCl. We also found that incubation with increased concentrations of NaCl altered STAT6 phosphorylation upon IL4/IL13 stimulation. We propose that NaCl-induced hypertonicity alters chromatin modifications and signaling cascades important for the expression of genes essential for AAM polarization and function.