Abstract
The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two main mechanisms, the classical and trans-signalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 trans-signalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.
Highlights
Extracellular vesicles (EVs), such as exosomes and microvesicles, are endogenous nano-sized vesicles that are released by many cell types and mediate intercellular communication under both physiological and pathophysiological conditions [1]
The interleukin 6 (IL6) trans-signalling pathway as a therapeutic target for muscle pathology Cellular responsiveness towards IL6 or IL6/interleukin 6 receptor (IL6R) complexes is dependent on the ratio between IL6R and IL6 signal transducer (IL6ST) protein levels in cells [58]
We identified the IL6 trans-signalling pathway as a therapeutic target for muscle-related pathologies, and for Duchenne muscular dystrophy (DMD)
Summary
Extracellular vesicles (EVs), such as exosomes and microvesicles, are endogenous nano-sized vesicles that are released by many cell types and mediate intercellular communication under both physiological and pathophysiological conditions [1]. EVs have been extensively studied as delivery vehicles for therapeutics, as they can transport a multitude of molecules between cells (including nucleic acids, proteins, and lipids) [2,3,4,5,6]. It was previously shown that EVs can be engineered to carry biologically active molecules (both targeting ligands and/or therapeutic proteins), by fusing them to EV-associated proteins [3, 13,14,15,16] This strategy can be used to express decoy receptors on the surface of EVs, with the capability of binding to specific signalling molecules with high affinity and specificity, and thereby blocking their intercellular signalling cascades [16, 17]. This approach presents the opportunity for the modulation of inflammation by targeting key cytokines, such as interleukin 6 (IL6)
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