Gold Nanoparticles Modulate BCG-Induced Innate Immune Memory in Human Monocytes by Shifting the Memory Response towards Tolerance

Abstract

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.

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.…”

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

“…At variance with the tolerance induced by LPS priming, monocytes primed with BCG showed an enhanced production of inflammatory (IL-6 and TNF-α) and anti-inflammatory cytokines (IL-1Ra and IL-10) when challenged with LPS. Although Au NP did not have a direct effect in inducing a memory response per se , when monocytes were primed with BCG and Au NP together, a reduction in cytokine production in response to LPS challenge could be observed, compared to that in cells primed with BCG alone, suggesting that Au NP interfered with the induction of memory by BCG and shifted the memory response of monocytes toward a tolerant phenotype ( 110 ) ( Figure 1 , bottom part). This study provides the first evidence that Au NP can influence the development of innate immune memory triggered by microbial molecules or vaccines and affect the monocyte response to subsequent challenges.…”

Impact of Gold Nanoparticles on the Functions of Macrophages and Dendritic Cells

“…The possible explanation for this could be either alteration of the mitochondrial content and cristae density or alteration of the respiratory substrate transport system or alteration of the respiratory chain complex activity or a combination of these parameters [ 33 ]. Benjamin et al have already hypothesised that AuNPs dependent alteration of innate immune memory in human monocytes might be explained by alterations in metabolic pathways [ 34 ]. Here, we confirm that AuNPs alter the metabolic response of BMDMs in response to secondary stimuli (LPS/IL-4).…”