Skip to main content

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

Nature biomedical engineering

Authors: David P Schrijver, Rutger J Röring, Jeroen Deckers, Anne de Dreu, Yohana C Toner, Geoffrey Prevot, Bram Priem, Jazz Munitz, Eveline G Nugraha, Yuri van Elsas, Anthony Azzun, Tom Anbergen, Laszlo A Groh, Anouk M D Becker, Carlos Pérez-Medina, Roderick S Oosterwijk, Boris Novakovic, Simone J C F M Moorlag, Aron Jansen, Peter Pickkers, Matthijs Kox, Thijs J Beldman, Ewelina Kluza, Mandy M T van Leent, Abraham J P Teunissen, Roy van der Meel, Zahi A Fayad, Leo A B Joosten, Edward A Fisher, Maarten Merkx, Mihai G Netea, Willem J M Mulder

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.

© 2023. The Author(s).

PMID: 37291433

Participating cluster members