Abstract
While silica nanoparticles have enabled numerous industrial and medical applications, their toxicological safety requires further evaluation. Macrophages are the major cell population responsible for nanoparticle clearance in vivo. The prevailing macrophage phenotype largely depends on the local immune status of the host. Whereas M1-polarized macrophages are considered as pro-inflammatory macrophages involved in host defense, M2 macrophages exhibit anti-inflammatory and wound-healing properties, but also promote tumor growth. We employed different models of M1 and M2 polarization: granulocyte-macrophage colony-stimulating factor/lipopolysaccharide (LPS)/interferon (IFN)-γ was used to generate primary human M1 cells and macrophage colony-stimulating factor (M-CSF)/interleukin (IL)-10 to differentiate M2 monocyte-derived macrophages (MDM). PMA-differentiated THP-1 cells were polarized towards an M1 type by LPS/IFN-γ and towards M2 by IL-10. Uptake of fluorescent silica nanoparticles (Ø26 and 41 nm) and microparticles (Ø1.75 μm) was quantified. At the concentration used (50 μg/ml), silica nanoparticles did not influence cell viability as assessed by MTT assay. Nanoparticle uptake was enhanced in M2-polarized primary human MDM compared with M1 cells, as shown by flow cytometric and microscopic approaches. In contrast, the uptake of microparticles did not differ between M1 and M2 phenotypes. M2 polarization was also associated with increased nanoparticle uptake in the macrophage-like THP-1 cell line. In accordance, in vivo polarized M2-like primary human tumor-associated macrophages obtained from lung tumors took up more nanoparticles than M1-like alveolar macrophages isolated from the surrounding lung tissue. In summary, our data indicate that the M2 polarization of macrophages promotes nanoparticle internalization. Therefore, the phenotypical differences between macrophage subsets should be taken into consideration in future investigations on nanosafety, but might also open up therapeutic perspectives allowing to specifically target M2 polarized macrophages.
Highlights
Numerous types of nanomaterials, such as quantum dots or silica, carbon, zinc oxide, and gold nanoparticles, have been shown to induce inflammatory responses both in vitro and in vivo (Deng et al, 2011; Autengruber et al, 2014; Kusaka et al, 2014; Roy et al, 2014; Wu and Tang, 2014)
Macrophages differentiated from monocytes by GM-CSFor macrophage colony-stimulating factor (M-CSF)-treatment (GM-M /M-M ) were stimulated with LPS/IFN-γ or IL-10, respectively, to induce an M1 or M2 phenotype
Analysis of cytokine mRNA expression revealed that levels of tumor-necrosis factor (TNF) mRNA were elevated in LPS/IFN-γ treated GMM, correlating with the pro-inflammatory phenotype of these macrophages (Figure 1B)
Summary
Numerous types of nanomaterials, such as quantum dots or silica, carbon, zinc oxide, and gold nanoparticles, have been shown to induce inflammatory responses both in vitro and in vivo (Deng et al, 2011; Autengruber et al, 2014; Kusaka et al, 2014; Roy et al, 2014; Wu and Tang, 2014). Macrophages represent critical regulators of inflammatory processes and exhibit a high uptake potential for nanoparticles (Sica and Mantovani, 2012; Diesel et al, 2013; Klein et al, 2013; Amoozgar and Goldberg, 2014; Kusaka et al, 2014). C57BL/6 mice preferentially produce T helper type 1 (Th1) cytokines, such as interferon (IFN)-γ, whereas those from Balb/c mice favor T helper type 2 (Th2) cytokine production, e.g., interleukin (IL)-10. In addition to their distinct T-cell responses, in vitro investigations have demonstrated that macrophages from these mouse strains exert different reactions in response to the bacterial cell wall component and activator of the innate immune response lipopolysaccharide (LPS; Watanabe et al, 2004)
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