Abstract
Tumor-derived exosomes have been shown to induce various immunomodulatory effects. However, the underlying signaling pathways are poorly understood. Here, we analyzed the effects of ex vivo-derived exosomes on monocytic cell differentiation/activation using THP-1 cells as model. We isolated exosomes from various body fluids such as amniotic fluid, liver cirrhosis ascites, and malignant ascites of ovarian cancer patients. We observed that exosomes were internalized by THP-1 cells and induced the production of IL-1β, TNF-α, and IL-6. Analysis of the signaling pathways revealed a fast triggering of NFκB and a delayed activation of STAT3. Pharmacologic and antibody-blocking experiments showed that the initial production of IL-6 was instrumental for subsequent activation of STAT3. Importantly, triggering of cell signaling was not a unique property of tumor exosomes but was also observed with exosomes of noncancerous origin. Exosomal signaling was TLR-dependent as the knockdown of Toll-like receptor 2 (TLR2) and TLR4 blocked NFκB and STAT3 activation. Similar results were obtained with TLR-neutralizing antibodies. Exosomes also triggered the release of cytokines from mouse bone marrow-derived dendritic cells or macrophages. This process was MyD88-dependent, further supporting a role of TLR signaling. Our results suggest that exosomes trigger TLR-dependent signaling pathways in monocytic precursor cells but possibly also in other immune cells. This process could be important for the induction of immunosuppressive mechanisms during cancer progression and inflammatory diseases.
Highlights
Exosomes, secreted from cells, have immunomodulatory capacities
Biochemical analysis revealed that AS and amniotic fluid (AF) exosomes were positive for the established exosomal marker proteins HSP70, Annexin-1, and LAMP1 as well as the ESCRT component Tsg101 (Fig. 1B)
When THP-1 cells were stimulated with exosomes in the presence of anti-IL-6 or anti-IL-6 receptor antibodies no phosphorylation of STAT3 was observed (Fig. 3C)
Summary
Exosomes, secreted from cells, have immunomodulatory capacities. Results: NFB- and STAT3-mediated cytokine release is triggered by various types of ex vivo exosomes in a TLR-dependent fashion. Exosomes triggered the release of cytokines from mouse bone marrow-derived dendritic cells or macrophages This process was MyD88-dependent, further supporting a role of TLR signaling. Our results suggest that exosomes trigger TLR-dependent signaling pathways in monocytic precursor cells but possibly in other immune cells. This process could be important for the induction of immunosuppressive mechanisms during cancer progression and inflammatory diseases. Exosomes Trigger Cytokine Release via TLRs differentiation into myofibroblasts (28) They foster the interplay of stroma cells with breast tumor cells (29). These effects support tumor growth and suppress innate and adaptive immune responses It is presently unknown which signal pathways exosomes trigger in recipient cells to induce an immunosuppressive phenotype. We show that the initiation of this signaling is TLR-dependent and can be elicited by tumor-derived exosomes
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