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oai:repisalud.isciii.es:20.500.12105/164122024-05-27T19:32:34Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Schrijver, David P author Röring, Rutger J author Deckers, Jeroen author de Dreu, Anne author Toner, Yohana C author Prevot, Geoffrey author Priem, Bram author Munitz, Jazz author Nugraha, Eveline G author van Elsas, Yuri author Azzun, Anthony author Anbergen, Tom author Groh, Laszlo A author Becker, Anouk M D author Pérez-Medina, Carlos author Oosterwijk, Roderick S author Novakovic, Boris author Moorlag, Simone J C F M author Jansen, Aron author Pickkers, Peter author Kox, Matthijs author Beldman, Thijs J author Kluza, Ewelina author van Leent, Mandy M T author Teunissen, Abraham J P author van der Meel, Roy author Fayad, Zahi A author Joosten, Leo A B author Fisher, Edward A author Merkx, Maarten author Netea, Mihai G author Mulder, Willem J M author 2023-06-08 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. Nat Biomed Eng. 2023 Jun 8. 10.1038/s41551-023-01050-0 2157-846X Nature biomedical engineering 37291433 http://hdl.handle.net/20.500.12105/16412 Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.