Induction of dendritic cell-like phenotype in macrophages during foam cell formation

Abstract

Foam cell formation from monocyte-derived macrophages is a hallmark of atherosclerotic lesions. Aspects of this process can be recapitulated in vitro by exposing M-CSF-induced or platelet factor 4 (CXCL4)-induced macrophages to oxidized (ox) or minimally modified (mm) low density lipoprotein (LDL). We measured gene expression in peripheral blood mononuclear cells, monocytes, and macrophages treated with CXCL1 (GRO-α) or CCL2 (MCP-1), as well as foam cells induced by native LDL, mmLDL, or oxLDL using 22 Affymetrix gene chips. Using an advanced Bayesian error-pooling approach and a heterogeneous error model with a false discovery rate <0.05, we found 5,303 of 22,215 probe sets to be significantly regulated in at least one of the conditions. Among a subset of 917 candidate genes that were preselected for their known biological functions in macrophage foam-cell differentiation, we found that 290 genes met the above statistical criteria for significant differential expression patterns. While many expected genes were found to be upregulated by LDL and oxLDL, very few were induced by mmLDL. We also found induction of unexpected genes, most strikingly MHC-II and other dendritic cell markers such as CD11c. The gene expression patterns in response to oxLDL were similar in M-CSF-induced and CXCL4-induced macrophages. Our findings suggest that LDL and oxLDL, but not mmLDL, induce a dendritic cell-like phenotype in macrophages, suggesting that these cells may be able to present antigens and support an immune response.