Metal Oxide Nanoparticles in Therapeutic Regulation of Macrophage Functions

Abstract

Macrophages are components of the innate immune system that control a plethora of biological processes. Macrophages can be activated towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes depending on the cue; however, polarization may be altered in bacterial and viral infections, cancer, or autoimmune diseases. Metal (zinc, iron, titanium, copper, etc.) oxide nanoparticles are widely used in therapeutic applications as drugs, nanocarriers, and diagnostic tools. Macrophages can recognize and engulf nanoparticles, while the influence of macrophage-nanoparticle interaction on cell polarization remains unclear. In this review, we summarize the molecular mechanisms that drive macrophage activation phenotypes and functions upon interaction with nanoparticles in an inflammatory microenvironment. The manifold effects of metal oxide nanoparticles on macrophages depend on the type of metal and the route of synthesis. While largely considered as drug transporters, metal oxide nanoparticles nevertheless have an immunotherapeutic potential, as they can evoke pro- or anti-inflammatory effects on macrophages and become essential for macrophage profiling in cancer, wound healing, infections, and autoimmunity.

Keywords: immunotherapy; inflammation; macrophages; metal oxides; nanoparticles; signal transduction.

Figure 1

Macrophage polarization: M1 (classical, pro-inflammatory) and M2 (alternative, anti-inflammatory). M1 polarization can be triggered by lipopolysaccharides (LPS) and/or interferon gamma (INFγ). M1 macrophages express high CD80 and MHCII and produce pro-inflammatory cytokines to stimulate the innate and adaptive immune activity of monocytes, neutrophils, T- and B-lymphocytes. M2 cells are characterized by surface markers Ym1, CD206, and mannose receptor, as well as by cytokines that have a potential for immunosuppression and tissue regeneration. Tumor-associated macrophages develop an M2 phenotype and promote the immune escape of tumor cells.

Figure 2

Systemic and local routes of NPs delivery and distribution. (A). At the systemic level, NPs can enter the organism with water/food/drug uptake or i.v. injections. Local contact with NPs occurs from skin contact, inhalation, and tumor therapy. Eventually, NPs are distributed throughout the organism in a cell free form or can be phagocytized. (B). When the phagocytized NPs are moving with the blood flow, they are accumulated in the heart. Air NPs primarily interact with alveolar MФs. Inhaled and injected NPs can penetrate the blood-brain barrier where they contact with microglia. The ultimate destinations of NPs are the liver and the spleen.

Figure 3

Molecular mechanisms of pro- and anti-inflammatory effects of NPs on MФs. NPs interact with cell surface receptors and can enter the cells via endocytosis/pinocytosis. (A). Pro-inflammatory signaling of NPs activates Toll-like (TLRs), Fcγ, and SR-A1 and MARCO scavenger receptor pathways with involved downstream MAPK/mTOR cascades and transcription factors STATs, NFkB and IRFs. NPs stimulate cytokine production and release, inflammasome formation, and phagocytic activity, thereby prompting M1 polarization. The immunostimulatory effect of NPs re-shapes the immunosuppressive microenvironment and boosts up antimicrobial or anticancer immunity. (B). The anti-inflammatory activity of NPs is applied to M1 committed MФs, as in chronic inflammatory disorders, autoimmunity, and neurodegeneration. NPs activate transcription factor PPARγ and arginase 1 to inhibit pro-inflammatory NFκB, modulate Jak/STAT pathway, and limit inflammation.