Lecture: Dr. Mateja Manček Keber: Extracellular vesicles as modulators of innate immune response
Lecture title: Extracellular vesicles as modulators of innate immune response
Lecturer: Dr. Mateja Manček Keber
When & Where: Monday, June 5, 2023 at 1 p.m., Great Lecture Hall
Receptors of innate immunity recognize pathogen-associated molecular patterns (PAMPs). Among the more important receptors is the family of Toll-like receptors-TLRs, especially TLR4. TLR4 and its co-receptor MD-2 recognize bacterial lipopolysaccharide (LPS). Subsequent activation of the adapter protein MyD88-dependent signaling pathway leads to the synthesis of inflammatory mediators. In several articles, we have identified amino acid residues important for LPS recognition, established MD-2 structural model and the mechanism of TLR4/MD-2 activation. In recent years, it has become evident that TLRs detect not only PAMPs, but also endogenous damage-associated molecular patterns (DAMPs). We identified oxidized phospholipids as one of the important activators.
Extracellular vesicles (EVs) are nanometer sized membrane vesicles that are released from cells. They are important because they transmit information between donor and target cells, thus influencing their function. The information they carry can be proteins, nucleic acids, lipids or sugars. EVs are detected in all body fluids. When cells are under stress, they release higher amounts of EVs. Chronic diseases are associated with inflammation, which can also be driven by oxidative stress. Lipids with unsaturated acyl chains are highly prone to oxidation by reactive oxygen compounds and can be released from cells in EVs. We have shown that EVs, released from cells under oxidative stress, can activate the TLR4/MD-2 receptor complex and the expression of inflammatory cytokines. The activity of EVs depended on the oxidation of phospholipids by lipoxygenase and the activity of phospholipases. Since the formation of oxidized lysophospholipids is enzyme driven, inhibition of enzymes could be used for the treatment of certain chronic diseases. In recent years, role of EVs in the development of cancer and the spread of cancer to other tissues has been described. In some cancers (e.g. Waldenstrom's macroglobulinemia – B cell lymphoma), activated lymphoma cells affect other non-transformed cells by releasing inflammatory cytokines. We have shown that by secreting EVs, these cancer cells can also transmit active signaling complexes, such as MyD88, to the surrounding cells, and promote inflammation in target cells without receptor activation. The search for inhibitors of inflammatory signaling pathways in cancer is in full swing, but we set out to inhibit MyD88 at the level of pre-mRNA molecule using exon skipping technology.
The lecture will be held in English.