Glioma-associated microglia and macrophages (GAMs) comprise up to 30% of the brain tumor mass, making them substantial contributors to the tumor environment. Once within the tumor niche, infiltrating GAMs are quickly converted to pro-tumorigenic phenotypes that enhance glioma growth and migration. Here we have characterized the role of Na + /H+ exchanger isoform-1 (NHE1) in the bidirectional communication between glioma cells and microglia. NHE1 protein expression was increased in tumor xenographs in both microglia and glioma cells. We found that microglia cells exposed to glioma-conditioned medium increased their NHE1 expression, as well as expression of the M1 marker iNOS and the M2 marker Arg1. This is in accordance with the mixed activation profile observed with GAMs. The levels of a panel of other candidates were also evaluated, revealing a large increase in expression of the cytokines IL6, IL10, and TGFβ as well as membrane type 1-matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase 9. Regulation of all these proteins was abolished when NHE1 protein in microglia was inhibited with the selective NHE1 inhibitor HOE642. We next looked at the communication from glioma-stimulated microglia back to glioma cells. Glioma cells were exposed to conditioned medium from glioma-stimulated microglia grown with or without the NHE1 inhibitor HOE642. Glioma cells treated with glioma/microglia conditioned medium showed increased levels of phosphylated-Akt, increased proliferation, and enhanced migration, but not if microglial NHE1 function had been blocked by HOE 642. Our results show that NHE1 plays important roles in both the activation of microglia in response to tumor-secreted signals as well as microglial production of secreted signals which stimulate tumor progression. Thus, NHE1 is a promising therapeutic target for the treatment of glioma. Funding sources include NIH grants R01NS075995 and R01NS048216, the HEADRUSH Brain Tumor Research Professorship, the Roger Loff Memorial GBM Research Fund, and Department of Neurological Surgery.
