Silver nanoparticle immunomodulatory potential in absence of direct cytotoxicity in RAW 264.7 macrophages and MPRO 2.1 neutrophils

Abstract

Engineered nanomaterials (ENM) are being used in a wide range of consumer products and pharmaceuticals; hence, there is an increasing risk for human exposure and potential adverse outcomes. The immune system, vital in host defense and protection against environmental agents, is typically initiated and executed by innate effector immune cells including macrophages and neutrophils. Previous literature has reported the immune system as a major target of ENM toxicity; however, there is inconsistency regarding the immunotoxicity of ENM. This could be attributed to differences in ENM physicochemical properties, cellular models examined, biocorona formation, etc. Thus, the current study examined the toxicity and immunomodulatory effects of silver nanoparticles (AgNP), one of the most utilized ENM in consumer and medical products, in two key innate immune cell models, e.g. RAW 264.7 cells (macrophages) and differentiated MPRO 2.1 cells (promyelocytes/neutrophils). The results showed that despite a generation of reactive oxygen species, exposure to 20 nm citrate-coated AgNP was not associated with major oxidative damage, inflammatory responses, nor cytotoxicity. Nevertheless, and most importantly, pre-exposure to the AgNP for 24 h enhanced RAW 264.7 cell phagocytic ability as well as the release of inflammatory cytokine interleukin-6 in response to lipopolysaccharide (LPS). In MPRO 2.1 cells, AgNP pre-exposure also resulted in enhanced phagocytic ability; however, these cells manifest reduced cell degranulation (elastase release) and oxidative burst in response to phorbol myristate acetate (PMA). Taken together, these findings indicated to us that exposure to AgNP, despite not being directly (cyto)toxic to these cells, had the potential to alter immune cell responses. The findings underscore the import of assessing immune cell function post-exposure to ENM beyond the standard endpoints such as oxidative stress and cytotoxicity. In addition, these findings further illustrate the importance of understanding the underlying molecular mechanisms of ENM-cellular interactions, particularly in the immune system.

Modulatory Role of Silver Nanoparticles and Mesenchymal Stem Cell–Derived Exosome-Modified Barrier Membrane on Macrophages and Osteogenesis

“…For example, Park et al found that RAW264.7 cells exposed to different concentrations of Ag nanoparticles showed a dose- and time-dependent decrease of cell viability ( Park et al, 2010a ). In another study, RAW264.7 cells were used to test Ag toxicity, and the results indicated that Ag showed no significant toxicity even at high concentrations ( Alsaleh et al, 2019 ). We next fabricated an exosome-based and Ag-guided biomembrane scaffold to regulate the early osteogenesis environment.…”

In vitro study on the immunomodulatory effects of differently functionalized silver nanoparticles on human peripheral blood mononuclear cells

“…Such results may be easily misinterpreted as an antiinflammatory effect, while decrease in cytokine expression may be actually caused by cytotoxic action of AgNPs, especially at higher concentrations [1,21]. This was also highlighted in recent study by Alsaleh et al who investigated AgNPs oxidative stress induction prior to determination of phagocytic ability of polymorphonuclear cells (PMNCs) [22]. After exposure to citrate-coated AgNPs for 24 h, applied concentrations that did not induce significant cell damages were used to assess phagocytic ability [22].…”

<p>Silver Nanoparticles for the Therapy of Tuberculosis</p>

“…Thus, although exposure of neutrophils to AgNP (50 µg/mL) was associated with reduced neutrophilic degranulation (elastase release) and oxidative burst, the overall phagocytic activity was enhanced. 251 In the same study, preexposure of macrophages (RAW 264.7) to AgNP, stimulates the release of inflammatory cytokine interleukin-6 as well as enhancement of phagocytic ability in response to lipopolysaccharide stimulation. 251 Also, the exposure of J774 A1 murine macrophage to AgNPs resulted in early activation of the inflammatory response by up-regulation of IL-1, IL-6, and TNF-a genes, but in a lesser amount compared with AuNPs.…”

“…251 In the same study, preexposure of macrophages (RAW 264.7) to AgNP, stimulates the release of inflammatory cytokine interleukin-6 as well as enhancement of phagocytic ability in response to lipopolysaccharide stimulation. 251 Also, the exposure of J774 A1 murine macrophage to AgNPs resulted in early activation of the inflammatory response by up-regulation of IL-1, IL-6, and TNF-a genes, but in a lesser amount compared with AuNPs. 252 Therefore, taking into account the divergent data regarding the immune impact of AgNPs, a better understanding of activation or suppression of immune cell pathways and functions following AgNPs needs to carry before a clinical-functional significance in the context of the complex inflammatory environment associated with mycobacterial infections to be drawn.…”