Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/16412
Título
Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.
Autor(es)
Schrijver, David P | Röring, Rutger J | Deckers, Jeroen | de Dreu, Anne | Toner, Yohana C | Prevot, Geoffrey | Priem, Bram | Munitz, Jazz | Nugraha, Eveline G | van Elsas, Yuri | Azzun, Anthony | Anbergen, Tom | Groh, Laszlo A | Becker, Anouk M D | Pérez-Medina, Carlos | Oosterwijk, Roderick S | Novakovic, Boris | Moorlag, Simone J C F M | Jansen, Aron | Pickkers, Peter | Kox, Matthijs | Beldman, Thijs J | Kluza, Ewelina | van Leent, Mandy M T | Teunissen, Abraham J P | van der Meel, Roy | Fayad, Zahi A | Joosten, Leo A B | Fisher, Edward A | Merkx, Maarten | Netea, Mihai G | Mulder, Willem J M
Fecha de publicación
2023-06-08
Cita
Nat Biomed Eng. 2023 Jun 8.
Idioma
Inglés
Tipo de documento
journal article
Resumen
Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.
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