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.