Studies On Class A Scavenger Receptor Regulating Macrophages Polarization In Glioma Microenvironment

Gliomas are the most frequent primary tumor of the central nervous system. Two main reasons for easy relapse and high malignancy in patients with gliomas are neovascularization and a massive stromal cells infiltration. As a major kind of stromal cells, macrophages have attracted widespread attention. Polarized macrophages can be generally classified into two main groups:classically activated macrophages (or M1-like) and alternatively activated macrophages (or M2-like). Scavenger receptor A (SR-A), an important pattern recognition receptors in macrophages with a lot of ligands, has multiple biological functions in diseases by regulating macrophage phagocytosis, apoptosis, and cytokines secretion. Recently studies showed that SR-A is strongly associated with tumor initiation and development. In this study, we identify the relationship between SR-A and the polarization of glioma-associated macrophages, and then seek its potential ligand in glioma microenvironment. Therefore, targeting SR-A may provide viable strategies in combating glioma.In order to clarify the role of SR-A in glioma, we co-cultured peritoneal macrophages from SR-A+/+ and SR-A-/- mice with GL261 cells. Compared with SR-A+/+ macrophages, SR-A-/- macrophages showed an enhanced ability to induce tumor cell proliferation, migration and invasion. Next, we examined the polarization of macrophages in this co-culture system, and found that the SR-A knockout induced glioma promotion is caused by a skewed M2-like polarization of macrophage. Furthermore, western blotting analysis also showed that the SR-A deletion in peritoneal macrophages caused a significant increase of STAT3,6 phosphorylation.Then, we injected GL261 cells into SR-A+/+ mice to construct orthotopic glioma models. To determine whether there are potential SR-A ligands in the glioma microenvironment, we cultured both SR-A+/+ and SR-A-/- macrophages with a sucrose density gradient centrifuged brain homogenate supernatant (brain lysate) from mice. We detected macrophage cytokines expression activity in both co-cultured with orthotopic glioma and sham-operated brain lysates. RT-PCR results suggested that something in fraction 2 and 5 can affect the polarization of macrophages. Then we used mass spectrometry to analysis the fraction. Combining the mass spectrometry results and the previous studies, we suspected that the heat shock protein family may have a closer relationship with SR-A in macrophages and regulates the glioma progression. Our results also indicated that HSP70 could induce M1-like polarization and prevent macrophagial activity of promoting glioma cell migration and invasion through SR-A.We can conclud that SR-A in macrophages negatively regulated glioma growth through mediating macrophages to a Ml phenotype and decreasing STAT3,6 phosphorylation in macrophages. Moreover, we also found that glioma mesenchymal HSP70 could inhibit the growth of glioma. Therefore, SR-A and HSP70 are expected to become new targets for the treatment of glioma.