Accumulation of hypoxia imaging probe “ 18 F-FMISO” in macrophages depends on macrophage polarization in addition to hypoxic state

Abstract

Objective

Macrophages play an essential role in immune response, and are closely related to the progression of diseases such as cancer and atherosclerosis. Macrophages polarize to M1 or M2 type, which is related to the environmental hypoxic state. Previously, we found that ¹⁸F-FMISO uptake varied according to expression levels of biomolecules such as glutathione S-transferase P1 (GST-P1), which catalyzes the conjugation of glutathione to ¹⁸F-FMISO metabolites, and multidrug resistance-associated protein 1 (MRP1), which exports glutathione-¹⁸F-FMISO metabolite conjugates out of cells. However, the relationship between macrophage polarization and ¹⁸F-FMISO accumulation remains unclear.

Methods

Mouse peritoneal macrophages were polarized to either the M1 or M2 type, and were treated with ¹⁸F-FMISO. Then, their radioactivity after a 4 h incubation period under normoxic (21% O₂) or hypoxic (1% O₂) condition was measured. GST-P1 and MRP1 expression levels were measured by qRT-PCR.

Results

M2 macrophages exhibited a significantly higher uptake of ¹⁸F-FMISO than non-polarized (M0) macrophages, whereas M1 macrophages had a significantly lower uptake than M0 macrophages (M0: 1.05 ± 0.22, M1: 0.34 ± 0.02, M2: 4.17 ± 0.36 %dose/mg protein). The GST-P1 expression level in M1 macrophages was higher than that in M2 and M0 macrophages [GST-P1/β-actin normalized by M0: 9.0 ± 3.7 (M1), 1.2 ± 0.2 (M2)]. The MRP1 expression level in M1 macrophages was significantly higher than that in M2 and M0 macrophages [MRP1/β-actin normalized by M0 macrophages: 5.1 ± 2.1 (M1), 2.8 ± 1.0 (M2)].

Conclusions

¹⁸F-FMISO accumulation in macrophages may depend on the polarization state in addition to hypoxic condition.

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