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Published on: November 28, 2019
Nanostructured Microparticles Repolarize Macrophages and Induce Cell Death in an In Vitro Model of Tumour-Associated
Salma Al-Fityan1, Britta Diesel1, Thorben Fischer2
1Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbruecken, Germany.
Abstract:
Macrophages (MΦs) in their pro-inflammatory state (M1) suppress tumour growth, while tumour-associated MΦs (TAMs) can promote tumour progression. The aim of this study was to test the hypothesis that targeted delivery of the immune activator poly(I:C) in aspherical silica microrods (µRs) can repolarize TAMs into M1-like cells. µRs (10 µm × 3 µm) were manufactured from silica nanoparticles and stabilized with dextran sulphate and polyethyleneimine. The THP-1 cell line, differentiated into MΦs, and primary human monocyte-derived MΦs (HMDMs) were treated with tumour-cell-conditioned medium (A549), but only HMDMs could be polarized towards TAMs. Flow cytometry and microscopy revealed elevated uptake of µRs by TAMs compared to non-polarized HMDMs. Flow cytometry and qPCR studies on polarization markers showed desirable effects of poly(I:C)-loaded MPs towards an M1 polarization. However, unloaded µRs also showed distinct actions, which were not induced by bacterial contaminations. Reporter cell assays showed that µRs induce the secretion of the inflammatory cytokine IL-1β. Macrophages from Nlrp3 knockout mice showed that µRs in concentrations as low as 0.5 µR per cell can activate the inflammasome and induce cell death. In conclusion, our data show that µRs, even if unloaded, can induce inflammasome activation and cell death in low concentrations.
Insights
Silica microrods loaded with poly(I:C) show potential for repolarizing tumor-associated macrophages (TAMs) towards an anti-tumor M1 state. Unloaded microrods also activate the inflammasome, inducing cell death in macrophages.
Area of Science:
- Immunology
- Materials Science
- Nanotechnology
Background:
- Pro-inflammatory M1 macrophages suppress tumors, while tumor-associated macrophages (TAMs) promote tumor progression.
- Targeted delivery systems are needed to modulate macrophage phenotypes for cancer therapy.
Purpose of the Study:
- To investigate if silica microrods (µRs) loaded with poly(I:C) can repolarize TAMs into M1-like cells.
- To evaluate the effects of unloaded µRs on macrophage activation and inflammasome pathways.
Main Methods:
- Fabrication of silica microrods (µRs) from silica nanoparticles.
- Polarization of human monocyte-derived macrophages (HMDMs) into TAMs using tumor-cell-conditioned medium.
- Assessment of µR uptake by TAMs using flow cytometry and microscopy.
- Evaluation of macrophage polarization markers via flow cytometry and qPCR.
- Analysis of inflammasome activation and cytokine secretion using reporter cell assays and macrophages from Nlrp3 knockout mice.
Main Results:
- TAMs exhibited higher uptake of µRs compared to non-polarized macrophages.
- Poly(I:C)-loaded µRs promoted M1 polarization markers.
- Unloaded µRs induced secretion of IL-1β and activated the inflammasome, leading to cell death at low concentrations.
- µR-induced inflammasome activation was confirmed in Nlrp3 knockout macrophages.
Conclusions:
- Silica microrods can effectively deliver poly(I:C) to TAMs, inducing M1-like repolarization.
- Even unloaded µRs possess intrinsic immunomodulatory properties, activating the inflammasome and causing macrophage cell death.
- These findings highlight the potential of silica microrods as versatile tools in cancer immunotherapy and macrophage-targeted therapies.
