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Review
. 2020 Dec 17;12(12):1222.
doi: 10.3390/pharmaceutics12121222.

Neutrophils and Macrophages as Targets for Development of Nanotherapeutics in Inflammatory Diseases

Affiliations
Review

Neutrophils and Macrophages as Targets for Development of Nanotherapeutics in Inflammatory Diseases

Yujie Su et al. Pharmaceutics. .

Abstract

Neutrophils and macrophages are major components of innate systems, playing central roles in inflammation responses to infections and tissue injury. If they are out of control, inflammation responses can cause the pathogenesis of a wide range of diseases, such as inflammatory disorders and autoimmune diseases. Precisely regulating the functions of neutrophils and macrophages in vivo is a potential strategy to develop immunotherapies to treat inflammatory diseases. Advances in nanotechnology have enabled us to design nanoparticles capable of targeting neutrophils or macrophages in vivo. This review discusses the current status of how nanoparticles specifically target neutrophils or macrophages and how they manipulate leukocyte functions to inhibit their activation for inflammation resolution or to restore their defense ability for pathogen clearance. Finally, we present a novel concept of hijacking leukocytes to deliver nanotherapeutics across the blood vessel barrier. This review highlights the challenges and opportunities in developing nanotherapeutics to target leukocytes for improved treatment of inflammatory diseases.

Keywords: cell targeting; inflammatory diseases; interactions of nanoparticles and cells; macrophages; nanomedicine; neutrophils.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Neutrophils and macrophages regulate inflammatory responses. In acute inflammation, neutrophils and monocytes are quickly released from the bone marrow and transmigrate into infected or injured tissues. These processes are regulated by macrophage colony-stimulating factor (M-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Monocytes differentiate in the tissues to become macrophages and may polarize to an M1 phenotype and release pro-inflammatory factors. Activated neutrophils secrete neutrophil extracellular traps (NETs) and proteases that are also involved in the functions of M1 macrophages during acute inflammation. In the phase of inflammation resolution, NETs and proteases are degraded and neutrophils become apoptotic, while macrophages efferocytose neutrophils and dead tissues. In addition, there is a macrophage transition from M1 to M2 during resolution of inflammation. If resolution of acute inflammation fails, persistent activation of neutrophils and macrophages mediates the pathogenesis of a wide range of vascular diseases. In a chronic inflammation phase, neutrophils and macrophages activate and regulate platelets and adaptive immunity to form a new homeostasis phase that leads to inevitable tissue damage and remodeling.
Figure 2
Figure 2
In situ nanoparticle targeting to activated neutrophils via Fcγ receptors. (A) Intravital microscopy of mouse cremaster muscle venules shows that neutrophil activation up-regulates Fcγ receptors. The resting neutrophils was established by no intrascrotal injection of TNF-a (0.5 mg per mouse) and the tail vein injection of Fcγ antibodies 3 h before performing intravital microscopy (top). Intrascrotal injection of TNF-a (0.5 mg per mouse) activated neutrophils. Alexa Fluor 647-labeled anti-mouse CD16/32 (red) and Alexa Fluor 488-labeled anti-mouse LY-6G (green) antibodies were intravenously injected to stain Fcγ receptors and neutrophils, respectively (bottom). Scale bars, 10 mm. (B) Percentages of co-staining between anti-mouse CD16/32 and anti-mouse LY-6G based on intravital images of (A). (C) Confocal laser scanning microscopy (CLSM) images of blood neutrophils from healthy mice or lipopolysaccharide (LPS)-challenged mice. Four hours after intraperitoneal LPS injection, doxorubicin conjugated bovine serum albumin nanoparticle (DOX-hyd-BSA) NPs were intravenously administered to a mouse. 3 h later, the mouse blood was collected, and neutrophils were isolated using anti-mouse LY-6G beads. Alexa Fluor 488-labeled antimouse LY- 6G antibody was used to label neutrophils. Scale bars, 10 mm. (D) Uptake of BSA NPs by blood leukocytes analyzed by flow cytometry. Neutrophils, T cells, monocytes, and natural killer (NK) cells were isolated from blood and stained by Alexa Fluor 647-labeled anti-mouse LY-6G, CD3, CD115, and CD335 antibodies, respectively. All data are expressed as means ± SD (three mice per group). (Reproduced from [105]; Published by American Association for the Advancement of Science (AAAS), 2019).
Figure 3
Figure 3
Targeting neutrophils and macrophages using nanoparticles for immunotherapies in inflammatory disorders. (a) Albumin nanoparticles loaded with piceatannol inhibit the neutrophil adhesion to endothelium, thus blocking neutrophil infiltration [93]. (b) Nanoparticles inhibit the functions of activated neutrophils and macrophages to reduce pro-inflammatory factors [149] and NETs release [145]. (c) Nanoparticles transform macrophages from the pro-inflammatory M1 phenotype (biomarkers of human leukocyte antigen-DR isotype (HLA-DR) and CD86) to anti-inflammatory M2 phenotype (biomarkers of CD163 and CD206) [133]. (d) DOX-loaded Nanoparticles induce neutrophil apoptosis to induce the resolution of inflammation [105]. (e) Nanoparticles activate neutrophil by up-regulating intracellular reactive oxygen species (ROS) level and CXCR2 to restore neutrophil pathogen clearance [166]. (f) Nanoparticles induce the transition of immunosuppressive M2 macrophages to immunoenhancement M1 macrophages to enhance phagocytosis [168].

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