BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis.

Autoimmune hepatitis is a chronic inflammatory disease in the liver with potential to the development of liver fibrosis. Recent evidences suggest that bone marrow derived mesenchymal stem cells (BMSCs) may exert its therapeutic activity through exosomes. Moreover, miR-223 is highly expressed in BMSCs and plays an important role in autoimmune diseases. Therefore, in this study, hepatoprotective role of BMSCs and miR-223 was investigated in both mice and hepatocytes. Liver antigen S100 was used to establish autoimmune hepatitis model in mice while LPS and ATP were used to establish cell injury model in hepatocyte. Before the experiments, BMSCs were infected with pre-miR-223 and transfected with miR-223 inhibitor respectively. Exosomes from bone marrow stem cells were isolated by ultracentrifugation. Liver injury was evaluated by serum levels of ALT and AST as well as liver histology. Inflammation and cell death were examined by inflammatory cytokines and lactase dehydrogenase respectively. Both BMSCs-exo and BMSCs-exomiR-223(+) significantly reversed either S100 or LPS/ATP induced injury in mice and hepatocytes. Meanwhile, the expressions of cytokines, NLRP3 and caspase-1 were also downregulated by BMSCs-exo and BMSCs-exomiR-223(+) at both protein and mRNA levels in mice and hepatocytes. Moreover, BMSCs-exomiR-223(-) reverses the effects of BMSCs-exo and BMSCs-exomiR-223(+) in mouse AIH and in hepatocytes. In conclusion, bone marrow stem cell derived exosomes can protect liver injury in an experimental model of autoimmune hepatitis and the mechanism could be related to exosomal miR-223 regulation of NLRP3 and caspase-1.

Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression.

The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (α-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to α-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5-year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets.

The S-100 protein causes an increase of intracellular calcium and death of PC12 cells.

The S-100 protein-PC12 cell interaction has been studied as a model system of the possible physiological role played by S-100 protein in the nervous system. The data reported demonstrate that S-100 exerts a cytotoxic action which eventually leads to PC12 cell death, regardless of the cell cycle phase. The effect is specific for the S-100 isoforms, which are made up of two identical subunits and is abolished by a monoclonal antibody directed against the same isoforms. Other isoforms and/or calcium-binding proteins, such as troponin or calmodulin, do not induce the same effects. The action of S-100 on cell viability is not detectable in other cell lines of different embryological origin, such as 3T3, L1210, GH3. S-100 causes a rapid and considerable increase (two- to three-fold) of intracellular Ca2+ concentration in PC12 cells accompanied by cytostatic and cytotoxic action. It is postulated that this action also occurs in vivo, as part of the physiological action of this protein.