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

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.