KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

Abstract

Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca2+-activated K+ channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma.

Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia

“…C). The later findings corroborate a recent report that K Ca 3.1 inhibition with TRAM‐34 can switch the phenotype of glioma infiltrating microglia/macrophages away from a tumor‐promoting to a more pro‐inflammatory anti‐tumor phenotype (Grimaldi et al, ).…”

Periostin Promotes Scar Formation through the Interaction between Pericytes and Infiltrating Monocytes/Macrophages after Spinal Cord Injury

“…46,47 Even after CNS injury, infiltrating monocytes/macrophages have been reported to exhibit chemotactic responses via phosphorylation of FAK. 48,49 These findings suggest that the POSTN-integrin axis is associated with the migration potential of monocytes/macrophages through the FAK/Akt pathway in the injured spinal cord. In addition, during the process of ischemic heart remodeling, the activation of FAK signaling in macrophages was found to promote the scar formation, 50 supporting the notion that the POSTN-integrin axis in monocytes/macrophages is also related to the scar formation after the CNS injury.…”

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

“…Interestingly, both glioma and infiltrating GAMs express the Ca 2+ -activated K + channels (KCa3.1), whose inhibition using 1-(2-chlorophenyl) diphenylmethyl-1H-pyrazole (TRAM-34) induced a switch of GAMs toward a pro-inflammatory, antitumor phenotype [60] . In addition, in vivo treatments with TRAM-34 significantly decreased the extent of tumor growth in glioma-bearing mice [60] . Moreover, stimulation of microglia with pro-inflammatory IL-12 is associated with increased phagocytic activity [61] .…”