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

Schrijver, DP;Röring, RJ;Deckers, J;de Dreu, A;Toner, YC;Prevot, G;Priem, B;Munitz, J;Nugraha, EG;van Elsas, Y;Azzun, A;Anbergen, T;Groh, LA;Becker, AMD;Pérez-Medina, C;Oosterwijk, RS;Novakovic, B;Moorlag, SJCFM;Jansen, A;Pickkers, P;Kox, M;Beldman, TJ;Kluza, E;van Leent, MMT;Teunissen, AJP;van der Meel, R;Fayad, ZA;Joosten, LAB;Fisher, EA;Merkx, M;Netea, MG;Mulder, WJM;

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.