Abstract
Interleukin-6 (IL-6) signaling is a crucial regulatory event important for many biological functions, such as inflammation and tissue regeneration. Accordingly, several pathological conditions are associated with dysregulated IL-6 activity, making it an attractive therapeutic target. For instance, blockade of IL-6 or its α-receptor (IL-6R) by monoclonal antibodies has been successfully used to treat rheumatoid arthritis. However, based on different signaling modes, IL-6 function varies between pro- and anti-inflammatory activity, which is critical for therapeutic intervention. So far, three modes of IL-6 signaling have been described, the classic anti-inflammatory signaling, as well as pro-inflammatory trans-signaling, and trans-presentation. The IL-6/IL-6R complex requires an additional β-receptor (gp130), which is expressed on almost all cells of the human body, to induce STAT3 (signal transducer and activator of signal transcription 3) phosphorylation and subsequent transcriptional regulation. In contrast, the IL-6R is expressed on a limited number of cells, including hepatocytes and immune cells. However, the proteolytic release of the IL-6R enables trans-signaling on cells expressing gp130 only. Here, we demonstrate a fourth possibility of IL-6 signaling that we termed joint reconstituted signaling (JRS). We show that IL-6R on extracellular vesicles (EVs) can also be transported to and fused with other cells that lack the IL-6R on their surface. Importantly, JRS via EVs induces delayed STAT3 phosphorylation compared to the well-established trans-signaling mode. EVs isolated from human serum were already shown to carry the IL-6R, and thus this new signaling mode should be considered with regard to signal intervention.
Highlights
Blockade of IL-6 signaling is a promising strategy for the treatment of chronic inflammatory conditions such as rheumatoid arthritis [1]
Crucial for the understanding of IL-6 biology is the discovery of three different signaling modes that can be induced by IL-6 and subsequent STAT3 phosphorylation: (i) Classic signaling refers to cells expressing the IL-6 receptor (IL-6R) together with gp130; (ii) Trans-signaling depends on the proteolytic release of the IL-6R, which in complex with IL-6 can bind and
We could previously show that IL-6R containing extracellular vesicles (EVs) are released by cells deficient for the two main sheddases ADAM10 and ADAM17 [22]
Summary
Blockade of IL-6 signaling is a promising strategy for the treatment of chronic inflammatory conditions such as rheumatoid arthritis [1]. Cells 2020, 9, 1307; doi:10.3390/cells9051307 www.mdpi.com/journal/cells least partial shedding of the full-length IL-6R (Fig D, fl IL-6R) to a soluble form of the IL-6R (Fig D, sIL-6R), indicating at least a partial type 1 transmembrane orientation of the receptor on vesicles. As the majority of the IL-6R remained at the vesicular surface after meprin α incubation in the given time, the presence of a mixture of exosomes and ectosomes in our purified EVs that carry the full-length IL-6R in different orientations is likely. Cells 2020, 9, 1307 the stability of the full-length receptor on EVs, and incubated the purified vesicles for 24 h at 37 °C in PBS (Figure 1E). No obvious cleavage fragments appeared over 24 h neither at ~70 kDa
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