4.8 Article

Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

Journal

BIOMATERIALS
Volume 266, Issue -, Pages -

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2020.120435

Keywords

Decoy receptors; IL6; Inflammation; Extracellular vesicles; Exosomes; Muscle

Funding

  1. Oxford University Press John Fell Fund
  2. Evox Therapeutics
  3. University Challenge Seed Fund (UCSF)
  4. MRC Confidence in Concept
  5. Muscular Dystrophy Association
  6. Muscular Dystrophy UK
  7. Ricerca Finalizzata
  8. Ateneo Sapienza
  9. Swedish Medical Research Council
  10. Swedish Strategic Foundation of Medical Research - SSF-IRC, FormulaEx

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IL6 is a key mediator of inflammation that activates target cells through classical and trans-signalling pathways. Engineered EVs expressing IL6ST decoy receptors can selectively inhibit the IL6 trans-signalling pathway, providing a potential therapeutic target for chronic inflammation.
The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle patho-physiology. 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.

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