E. Marion Schneider, PhD

University Hospital Ulm

Division of Experimental Anesthesiology

In psychiatric diseases, the selective contribution of sterile vs. infection associated inflammation has remained a matter of discussion. A major event in sterile inflammation is mediated by the ATP-responsive P2X7 ion channel, highly expressed in activated macrophages. ATP stimulation of macrophages leads to an increased release of IL-1β bearing, plasma membrane-derived microparticles (MP). Using sensitive ELISA, we found that IL-1β is the leading cytokine in cerebrospinal fluid of patients with affective disorders (AF), and schizophrenia (SZ). Investigation of in vivo activated and in vitro cultured macrophages from patients proved the presence of IL-1β in these MP, which were released upon ATP stimulation. ATP stimulation also led to quantitative changes in the miRNA species which turned out to be patient specific.  MPs from patients’ isolates with affective disorders were high in miRNA21 expression and further upregulated miRNA-21 as well as anti-inflammatory miR146a by ATP treatment. The ATP-guided upregulation of hypoxia-related miRNA-93 and miRNA-210 was found in both AF and SZ derived samples as well control MP preparations established from patients with overtraining syndrome and malignancies. Based on the unique stability of miRNA species and their valuable diagnostic properties in regulating cell signaling, such MPs may well explain functional changes in target tissues following MP uptake and/receptor mediated fusion events.  Results demonstrate that both: Infection/inflammation as well as hypoxia inducible miRNA species appear to be characteristic for AF patients’ MPs but not SZ patients’ derived samples. Both, miRNA-21 and miRNA-146a may provide important signatures to distinguish AF and SZ patients, and miRNA-16 may be relevant to follow psychiatric treatment. Although to different levels, all MP preparations provided evidence for hypoxia-related pathway activation, this is why a likely and selective relevance of mitochondrial dysfunction requires further investigations. The pattern of miRNA upregulation was apparently independent of the pro-inflammatory phenotype M1 or the anti-inflammatory phenotype M2, identified by flow cytometry and  CD-marker profiling. High HLA-class II, and Arginase 1 expression corresponded to an M1 phenotype, whereas anti-inflammatory macrophages presented with lower HLA-class II as well as higher CD206 and CD163 expression. In summary, MPs released by ATP from cultured macrophages may target inflammatory- as well as hypoxia-related pathways by their miRNA contents. Selective differences among patients groups may guide novel therapeutic and diagnostic approaches.