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.

Keywords: epigenetics; innate memory; macrophages; metabolism; monocytes; nanoparticles.

Figure 1

Nanoparticles as inducers of innate immune memory. Upper part: β-glucan or BCG-primed monocytes (left) have an enhanced glycolytic metabolic state and an impaired oxidative phosphorylation (OXPHOS). The tricarboxylic acid cycle (TCA) is fueled by metabolites derived from glutaminolysis, while pyruvate is mainly fermented into lactate. On the other hand, LPS-primed cells (right) preferentially use OXPHOS, and the glycolytic pathway generates pyruvate for fueling the TCA cycle. The epigenetic reprogramming occurring in β-glucan- and BCG-primed monocytes mainly encompasses histone methylation and acetylation and involves lncRNA, modifications that are lacking (or established late) in LPS-primed monocytes. NP (Au, pGr) may play a role in the induction and modulation of innate immune memory by regulating epigenetic and metabolic reprogramming of innate immune cells (dashed arrows). Lower part: BCG-primed monocytes (left) show an increased reactivity after a subsequent exposure to LPS. When monocytes are primed with BCG in the presence of Au NP, they show a reduced reactivity (right). Thus, Au NP are able to reduce the BCG-induced memory response in human primary monocytes by shifting the memory effect from potentiation/trained immunity to tolerance. By contrast, pGr (left) is able to prime directly murine BMDM, which responds to a subsequent LPS challenge with a potentiated reaction.