Morusin regulates the migration of M2 macrophages and GBM cells through the CCL4-CCR5 axis

Abstract

Background

Glioblastoma (GBM) is the most aggressive tumor in the central nervous system. Tumor-associated macrophage (TAMs) represent a major immune cell population in tumor microenvironment (TME) and exert immunosuppressive effects that impede GBM treatment. Morusin is a flavonoid extracted from mulberry trees and has anti-tumor properties against various cancers, including glioma. However, the impact of morusin on the TME of gliomas has not been explored.

Methods

We evaluated the effect of morusin on the tumor microenvironment using a mouse glioma model through in vivo and in vitro experiments. In vitro experiments demonstrated the effects of morusin on the viability of RAW264.7 and THP1 cells, and the migration ability of M2 macrophages. Furthermore, we investigated the effect of conditioned medium (CM) of morusin-treated M2 macrophages on the migration of glioblastoma cell lines GL261, U87, and U251.

Result

Morusin alleviated the GBM progression and prolonged mouse survival by inhibiting the ratio of macrophages to CD206⁺ macrophages. Mechanistically, we demonstrated that morusin could effectively inhibit the secretion of the chemokine CCL4 in M2 macrophage which consequently decreased CCL4-dependent CCR5 activation. This leads to the reduced migration of both macrophages and glioblastoma cells in TME. These findings provide a strong rationale for the development of morusin as a potential therapeutic agent for GBM, either as a standalone treatment or in combination with other immunotherapeutic strategies, and warrant further preclinical and clinical investigations.