Mehanizmi antiencefalitogenog dejstva etil-piruvata u eksperimentalnom autoimunskom encefalomijelitisu
Anti-encephalitogenic mechanisms of ethyl pyruvate in experimental autoimmune encephalomyelitis
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Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with proposed autoimmune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenetic mechanisms of the disease. Antigen presenting cells (APC) are major cells that are involved in the initiation of the autoimmune response against the CNS by activating CNS-specific naive CD4+ T cells. Consequently, these CD4+ T cells differentiate into effector T helper cells 1 (Th1) that produce interferon γ (IFN-γ) and Th17 cells that produce interleukin 17 (IL-17). Passing through the blood brain barrier, Th1 and Th17 cells arrive in the CNS where they become reactivated by the resident APC. Afterwards, other immune cells infiltrate the CNS, thus causing inflammation and tissue damage. The resident cells of the CNS, such as astrocytes and microglia, also contribute to the disease pathogenesis. Ethyl pyruvate (EP) is a lipophilic ester of pyruvic acid that possesses anti-oxidative and anti-inflammatory properties. The anti-encephalitogenic effect of EP in EAE and on cells of the CNS involved in the disease pathogenesis, were investigated in this study. Also, its in vitro and in vivo tolerogenic effect on dendritic cells (DC) was studied. Results showed that EP had a therapeutic effect on EAE when applied to the rats once a day, starting from the first clinical symptoms until their initial recovery. EP prevented immune cells infiltration into the CNS and inhibited T cell production of IL-17 in the spinal cord. Thus, EP restrained the inflammatory reaction in the CNS and therefore exerted its anti-encephalitogenic effect. Furthermore, treatment with EP led to the reduction of macrophages and microglia cell number, inhibition of astrocyte activity, as well as neuron destruction. Inhibition of HMGB1 (High-Mobility Group Box 1) molecule in activated macrophages/microglia was one of the mechanisms of the EP effects in the CNS. Moreover, in vitro treatment of stimulated macrophages with EP showed that EP had also an impact on APC. Treatment with EP led to reduced production of pro-inflammatory cytokines by macrophages as well as to downregulation of the expression of molecules relevant for antigen presentation. Furthermore, EP had a tolerogenic effect on the major APC, i.e. DC. Mice bone marrow derived DC were investigated. In vitro treatment of DC with EP inhibited their ability to efficiently present antigens, to activate T cells in allogeneic reaction, and to produce pro-inflammatory cytokines. Molecular mechanisms involved in the tolerogenic effects of EP on mice DC included stimulation of nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, increase of heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase 1 (NQO1) expression, and inhibition of nuclear factor κB (NF-κB) transcription factor activation. Also, EP-treated DC inhibited immune response in vivo induced with complete Freund’s adjuvant in mice. Finally, the tolerogenic effects of EP were demonstrated in human monocyte derived DC (MoDC) obtained from healthy individuals and MS patients. Results of this doctoral thesis show that EP ameliorates EAE and that is also an effective tolerogenic agent that shifts DC towards immune-suppressing phenotype. Thereby, EP has the potential to be applied in MS therapy. Its application could be direct or through generation of tolerogenic DC as a mean of cell-based immunotherapy. Future preclinical and clinical studies should be focused towards investigating the possible application of EP in MS therapy, as well as in other autoimmune and chronic inflammatory diseases.
Keywords:Experimental autoimmune encephalomyelitis; Multiple sclerosis; Ethyl pyruvate; Tolerogenic dendritic cells
Source:University of Belgrade, Faculty of Biology, 2019, 1-122
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