Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells
David P. Schrijver, Rutger J. Röring, Jeroen Deckers, Anne de Dreu, Yohana C. Toner, Geoffrey Prévot, Bram Priem, Jazz Munitz, Eveline G. Nugraha, Yuri van Elsas, Anthony Azzun, Tom Anbergen, Laszlo 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
Abstract
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.