Abstract

Innate immune memory, the ability of innate cells to react in a more protective way to secondary challenges, is induced by exposure to infectious and other exogeous and endogenous agents. Engineered nanoparticles are particulate exogenous agents that, as such, could trigger an inflammatory reaction in monocytes and macrophages and could therefore be also able to induce innate memory. Here, we have evaluated the capacity of engineered gold nanoparticles (AuNPs) to induce a memory response or to modulate the memory responses induced by microbial agents. Microbial agents used were in soluble vs. particulate form (MDP and the gram-positive bacteria Staphylococcus aureus; β-glucan and the β-glucan-producing fungi C. albicans), and as whole microrganisms that were either killed (S. aureus, C. albicans) or viable (the gram-negative bacteria Helicobacter pylori). The memory response was assessed in vitro, by exposing human primary monocytes from 2-7 individual donors to microbial agents with or without AuNPs (primary response), then resting them for 6 days to allow return to baseline, and eventually challenging them with LPS (secondary memory response). Primary and memory responses were tested as production of the innate/inflammatory cytokine TNFα and other inflammatory and anti-inflammatory factors. While inactive on the response induced by soluble microbial stimuli (muramyl dipeptide -MDP-, β-glucan), AuNPs partially reduced the primary response induced by whole microorganisms. AuNPs were also unable to directly induce a memory response but could modulate stimulus-induced memory in a circumscribed fashion, limited to some agents and some cytokines. Thus, the MDP-induced tolerance in terms of TNFα production was further exacerbated by co-priming with AuNPs, resulting in a less inflammatory memory response. Conversely, the H. pylori-induced tolerance was downregulated by AuNPs only relative to the anti-inflammatory cytokine IL-10, which would lead to an overall more inflammatory memory response. These effects of AuNPs may depend on a differential interaction/association between the reactive particle surfaces and the microbial components and agents, which may lead to a change in the exposure profiles. As a general observation, however, the donor-to-donor variability in memory response profiles and reactivity to AuNPs was substantial, suggesting that innate memory depends on the individual history of exposures.

Highlights

  • Immunological memory was long considered a distinctive trait of adaptive immunity, resulting in the capacity to mount a more rapid and more effective specific immune response to infectious challenges [1]

  • Here we have evaluated the capacity of AuNPs to modulate the innate memory response of human primary monocytes primed with different microbial agents in soluble vs. particulate forms (MDP and the gram-positive bacteria Staphylococcus aureus; b-glucan and the b-glucan-producing fungi C. albicans) and with a live microbial agent, using a realistic in vitro model based on human primary monocytes

  • This would contribute on one side to the implementation of a more thorough safety evaluation of AuNPs and, on the other hand, it could open the way to a targeted use of this nanomaterial for the therapeutic modulation of innate immunity/inflammation in several immune-related and inflammatory diseases

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Summary

Introduction

Immunological memory was long considered a distinctive trait of adaptive immunity, resulting in the capacity to mount a more rapid and more effective specific immune response to infectious challenges [1]. It is evident that organisms that only display innate immunity, the most ancient non-specific defensive system, can develop an immunological memory that allows them to resist better to various environmental pathogens and stressful events (e.g., heat, wounds) [2,3,4]. The innate memory responses, both tolerance and potentiation, are based on epigenetic and metabolic modifications, rather than in a general shift in gene transcription, and they should be understood as a medium-term functional reprogramming aimed at enhanced host defense (lasting several months to years in mammals) [6, 13,14,15,16]. Innate memory-inducing substances should be considered both from a safety perspective, in which excessive inflammation or immune suppression can be detrimental, and for their therapeutic potential, to downregulate or up-regulate excessive or insufficient innate immunity in different disease conditions

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