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

Yu Zhao; Xinying Zhou; Lei Hong; Jinyu Yao; Jinlin Pan; Shaheryar Shafi; Sami Siraj; Nafees Ahmad; Jiangang Liu; Rongchuan Zhao; Minxuan Sun

doi:10.1016/j.intimp.2024.113915

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

Int Immunopharmacol. 2024 Dec 30:147:113915. doi: 10.1016/j.intimp.2024.113915. Online ahead of print.

Authors

Yu Zhao¹, Xinying Zhou², Lei Hong³, Jinyu Yao⁴, Jinlin Pan⁵, Shaheryar Shafi⁶, Sami Siraj⁷, Nafees Ahmad⁸, Jiangang Liu⁹, Rongchuan Zhao¹⁰, Minxuan Sun¹¹

Affiliations

¹ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China. Electronic address: [email protected].
² School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China. Electronic address: [email protected].
³ Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Suzhou Science and Technology Town Hospital., No. 1 Lijiang Road, Suzhou 215153, China. Electronic address: [email protected].
⁴ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China. Electronic address: [email protected].
⁵ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China. Electronic address: [email protected].
⁶ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China.
⁷ Institute of Pharmaceutical Sciences, Khyber Medical University, Khyber Pakhtunkhwa 25100, Pakistan. Electronic address: [email protected].
⁸ Institute of Biomedical & Genetic Engineering, Islamabad 44000, Pakistan. Electronic address: [email protected].
⁹ Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Suzhou Science and Technology Town Hospital., No. 1 Lijiang Road, Suzhou 215153, China; Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215000, China. Electronic address: [email protected].
¹⁰ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China. Electronic address: [email protected].
¹¹ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China. Electronic address: [email protected].

PMID: 39740503
DOI: 10.1016/j.intimp.2024.113915

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.

Keywords: CCL4; Glioma; Migration; Morusin; TAM.