2,2'4,4'-Tetrabromodiphenyl Ether (PBDE-47) Modulates the Intracellular miRNA Profile, sEV Biogenesis and Their miRNA Cargo Exacerbating the LPS-Induced Pro-Inflammatory Response in THP-1 Macrophages

The 2,2'4,4'-tetrabromodiphenyl ether (PBDE-47) is one of the most prominent PBDEcongeners detected in the environment and in animal and human tissues. Animal modelexperiments suggested the occurrence of PBDE-induced immunotoxicity leading to differentoutcomes and recently we demonstrated that this substance can impair macrophage andbasophil activities. In this manuscript, we decided to further examine the effects induced byPBDE-47 treatment on innate immune response by looking at the intracellular expressionprofile of miRNAs as well as the biogenesis, cargo content and activity of human M(LPS)macrophage cell-derived small extracellular vesicles (sEVs). Microarray and in silico analysisdemonstrated that PBDE-47 can induce some epigenetic effects in M(LPS) THP-1 cellsmodulating the expression of a set of intracellular miRNAs involved in biological pathwaysregulating the expression of estrogen-mediated signaling and immune responses withparticular reference to M1/M2 differentiation. In addition to the cell-intrinsic modulation ofintracellular miRNAs, we demonstrated that PBDE-47 could also interfere with the biogenesisof sEVs increasing their number and selecting a de novo population of sEVs. Moreover,PBDE-47 induced the overload of specific immune relatedmiRNAs in PBDE-47 derived sEVs.Finally, culture experiments with naïve M(LPS) macrophages demonstrated that purifiedPBDE-47 derived sEVs can modulate macrophage immune response exacerbating the LPSinducedpro-inflammatory response inducing the overexpression of the IL-6 and the MMP9genes. Data from this study demonstrated that PBDE-47 can perturb the innate immuneresponse at different levels modulating the intracellular expression of miRNAs but also interferingwith the biogenesis, cargo content and functional activity of M(LPS) macrophage cellderivedsEVs.