Abcg1 geni susturulmuş makrofajların tümörle savaşan m1 fenotipine dönüşmesinin moleküler mekanizması

Macrophages that are major players of tumor immunity, are divided into two subgroups as M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. In general, M1 macrophages are potent tumor-fighting cells, whereas M2 macrophages display protumoral functions. ATP-binding Cassette Transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. We have recently shown that in the absence of ABCG1, macrophages shift from a tumor-promoting M2 phenotype to a tumor-fighting M1 phenotype within the tumor and suppress bladder cancer growth in vivo. The molecular mechanism through which ABCG1-deficiency shifts macrophages to a tumor fighting M1 phenotype is not known. To address the molecular mechanism, we analysed cell signalling in bone marrow-derived macrophages from Abcg1-/- mice. Compared to WT control, Abcg1-/- macrophages displayed reduced levels of Akt activation at basal level and after stimulation with the M1 signal LPS/IFNg or the M2 signal IL4 at different time points. Furthermore, in concordiance with the M1 bias, while Abcg1-/- macrophages stimulated with LPS/IFNg produced more TNFα compared to WT macrophages, after treatment with an Akt activator(SC79) the TNFa-production of Abcg1-/- and WT macrophages was comparable. These data suggest that the M1 bias of Abcg1-/- macrophages is mediated through the Akt signalling pathway. These findings not only deepen our mechanistic understanding of the M1/M2 switch in macrophages, but have the potential to open up new immunotherapeutic approaches for the treatment of cancer.