Induction of Innate Immune Memory by Engineered Nanoparticles in Monocytes/Macrophages: From Hypothesis to Reality

Abstract

The capacity of engineered nanoparticles to activate cells of the innate immune system, in particular monocytes and macrophages, is considered at the basis of their toxic/inflammatory effects. It is, however, evident that even nanoparticles that do not directly induce inflammatory activation, and are therefore considered as safe, can nevertheless induce epigenetic modifications and affect metabolic pathways in monocytes and macrophages. Since epigenetic and metabolic changes are the main mechanisms of innate memory, we had previously proposed that nanoparticles can induce/modulate innate memory, that is, have the ability of shaping the secondary response to inflammatory challenges. In light of new data, it is now possible to support the original hypothesis and show that different types of nanoparticles can both directly induce innate memory, priming macrophages for a more potent response to subsequent stimuli, and modulate bacteria-induced memory by attenuating the priming-induced enhancement. This evidence raises two important issues. First, in addition to overt toxic/inflammatory effects, we should consider evaluating the capacity to induce innate memory and the related epigenetic and metabolic changes in the immunosafety assessment of nanomaterials, since modulation of innate memory may be at the basis of long-term unwanted immunological effects. The other important consideration is that this capacity of nanomaterials could open a new avenue in immunomodulation and the possibility of using engineered nanomaterials for improving immune responses to vaccines and resistance to infections, and modulate anomalous immune/inflammatory reactions in chronic inflammatory diseases, autoimmunity, and a range of other immune-related pathologies.

Interaction between Macrophages and Nanoparticles: In Vitro 3D Cultures for the Realistic Assessment of Inflammatory Activation and Modulation of Innate Memory

“…While it is now clear that many NPs do not have the capacity for activating human monocytes if they are endotoxin-free [ 12 , 13 , 35 , 36 , 39 ], some data point to the possibility that they can prime monocytes and induce innate memory, which then changes the secondary reaction of cells to a subsequent stimulation [ 28 , 29 , 30 , 31 , 32 ]. We have examined the capacity of AuNPs to induce innate memory in monocytes from six different donors in 2D and 3D cultures.…”

“…While our understanding of innate memory is still largely incomplete, it is tempting to speculate that engineered NPs might be used for a targeted reprogramming of innate immunity for preventive and therapeutic scopes, such as in vaccination and immunotherapy [ 24 , 25 , 26 , 27 ]. Few recent studies show that indeed NPs may prime human monocytes and vertebrate/invertebrate macrophages and induce a modification of their response to a subsequent inflammatory challenge [ 28 , 29 , 30 , 31 , 32 ]. In this study, we have examined the memory-inducing capacity of AuNPs on human primary monocytes to define the most suitable conditions for a realistic evaluation.…”

Primary and Memory Response of Human Monocytes to Vaccines: Role of Nanoparticulate Antigens in Inducing Innate Memory

“…The present study did not yet address the mechanisms underlying the observed memory effects (studies currently ongoing), which is an issue of particular interest since the observed effects were different (increased vs. decreased production) depending on the cytokine under evaluation, implying concomitant changes at different levels, likely including epigenetic and metabolic regulation [ 51 , 52 , 53 , 54 , 55 ].…”

The Impact of Nanoparticles on Innate Immune Activation by Live Bacteria

“…Preliminary results indeed show that the memory response of human primary monocytes primed with live BCG and challenged with LPS, in terms of production of inflammatory TNFα and IL-6 and anti-inflammatory IL-1Ra and IL-10 cytokines was significantly reduced if Au NPs were present with BCG during priming [ 59 ]. These findings open the possibility of novel approaches of immunomodulation, in which NPs can be used for improving vaccine efficacy and general resistance to infections, and also for modulating and rebalancing the altered immune responses in a range of immune-related diseases, such as chronic inflammatory, degenerative, and autoimmune diseases [ 152 ].…”