Two‐Dimensional Transition Metal Dichalcogenides Trigger Trained Immunity in Human Macrophages through Epigenetic and Metabolic Pathways

Abstract

Trained immunity is a recently described phenomenon whereby cells of the innate immune system undergo long‐term epigenetic and/or metabolic reprogramming following a short‐term interaction with microbes or microbial products. Here, it is shown that 2D transition metal dichalcogenides (TMDs) trigger trained immunity in primary human monocyte‐derived macrophages. First, aqueous dispersions of 2D crystal formulations of MoS2 and WS2 are tested, and no cytotoxicity is found despite avid uptake of these materials by macrophages. However, when macrophages are pre‐exposed to TMDs, followed by a resting period, this causes a marked modulation of immune‐specific gene expression upon subsequent challenge with a microbial agent (i.e., bacterial lipopolysaccharides). Specifically, MoS2 triggers trained immunity through an epigenetic pathway insofar as the histone methyltransferase inhibitor methylthioadenosine reverses these effects. Furthermore, MoS2 triggers an elevation of cyclic adenosine monophosphate (cAMP) levels in macrophages and increased glycolysis is also evidenced in cells subjected to MoS2 training, pointing toward a metabolic rewiring of the cells. Importantly, it is observed that MoS2 triggers the upregulation of Mo‐dependent enzymes in macrophages, thus confirming that Mo is bioavailable in these cells. In conclusion, MoS2 is identified as a novel inducer of trained immunity. Thus, TMDs could potentially be harnessed as immunomodulatory agents.

Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective

“…Recent studies performed in the Graphene Flagship have revealed that 2D MoS 2 and WS 2 237 showed no cytotoxicity toward primary human monocyte-derived macrophages despite being readily internalized. 238 The authors found that TMDs triggered socalled trained immunity as shown also for graphene (see above). Thus, pre-exposure to TMDs ("training") followed by a resting period caused marked changes in immune-specific gene expression after challenging the cells with bacterial LPS.…”

“…Furthermore, MoS 2 triggered an elevation of cyclic adenosine monophosphate levels in macrophages and increased glycolysis was also observed upon MoS 2 "training", pointing toward a metabolic rewiring of the cells. 238 These results suggest that TMDs (especially MoS 2 ) could potentially be exploited for the modulation of immune responses. Even though MoS 2 nanosheets have been found to be internalized by macro-phages, other nonphagocytic cells may respond differently.…”

“…MoS 2 was found to trigger trained immunity through an epigenetic pathway as seen by the reversal of effects in cells exposed to the histone methyltransferase inhibitor methylthioadenosine. Furthermore, MoS 2 triggered an elevation of cyclic adenosine monophosphate levels in macrophages and increased glycolysis was also observed upon MoS 2 “training”, pointing toward a metabolic rewiring of the cells . These results suggest that TMDs (especially MoS 2 ) could potentially be exploited for the modulation of immune responses.…”

“…Recent studies performed in the Graphene Flagship have revealed that 2D MoS 2 and WS 2 showed no cytotoxicity toward primary human monocyte-derived macrophages despite being readily internalized . The authors found that TMDs triggered so-called trained immunity as shown also for graphene (see above).…”

Die hard: cell death mechanisms and their implications in nanotoxicology

“…However, it is noted that these effects were observed at high doses (200 µg/mL) of TMDs. In contrast, we have recently shown that nanosheets of WS 2 and MoS 2 were noncytotoxic towards primary human monocyte-derived macrophages ( Peng et al , 2022 ). These discrepancies could perhaps be explained by differences in the synthesis and physicochemical properties of the TMDs, and differences between primary cells and cell lines, and differences in the dose.…”