Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging–Guided Focused Ultrasound–Induced Blood–Brain Barrier Opening in a Mouse Glioblastoma Model

Yanrong Zhang, Jing Wang, Sara Natasha Ghobadi, Haiyan Zhou, Ai Huang, Marco Gerosa, Qingyi Hou, Olivier Keunen, Anna Golebiewska, Frezghi G. Habte, Gerald A. Grant, Ramasamy Paulmurugan, Kevin S. Lee, Max Wintermark*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

An orthotopically allografted mouse GL26 glioma model (Ccr2RFP/wt–Cx3cr1GFP/wt) was used to evaluate the effect of transient, focal opening of the blood–brain barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB opening was induced by magnetic resonance imaging (MRI)–guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not exhibit significant changes in cell numbers when compared with tumors in animals not receiving FUS. However, tumors that received two or three sessions of MRgFUS had significantly increased amounts of both CX3CR1-GFP and CCR2-RFP cells. The effect of MRgFUS on immune cell composition was also characterized and quantified using flow cytometry. Glioma implantation resulted in increased amounts of lymphocytes, monocytes and neutrophils in the brain parenchyma. Tumors administered MRgFUS exhibited increased numbers of monocytes and monocyte-derived TAMs. In addition, MRgFUS-treated tumors exhibited more CD80+ cells in monocytes and microglia. In summary, transient, focal opening of the BBB using MRgFUS combined with microbubbles can activate the homing and differentiation of monocytes and induce a shift toward a more pro-inflammatory status of the immune environment in glioblastoma.

Original languageEnglish
Pages (from-to)1082-1090
Number of pages9
JournalUltrasound in Medicine and Biology
Volume49
Issue number5
Early online date28 Jan 2023
DOIs
Publication statusPublished - May 2023

Keywords

  • Focused ultrasound
  • Glioblastoma
  • Magnetic resonance imaging–guided focused ultrasound
  • Microbubbles
  • Microglia and macrophage activation
  • Sterile inflammation
  • Tumor-associated macrophages and microglia

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