TY - JOUR
T1 - Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells
AU - Schrijver, David P.
AU - Röring, Rutger J.
AU - Deckers, Jeroen
AU - de Dreu, Anne
AU - Toner, Yohana C.
AU - Prevot, Geoffrey
AU - Priem, Bram
AU - Munitz, Jazz
AU - Nugraha, Eveline G.
AU - van Elsas, Yuri
AU - Azzun, Anthony
AU - Anbergen, Tom
AU - Groh, Laszlo A.
AU - Becker, Anouk M. D.
AU - Pérez-Medina, Carlos
AU - Oosterwijk, Roderick S.
AU - Novakovic, Boris
AU - Moorlag, Simone J. C. F. M.
AU - Jansen, Aron
AU - Pickkers, Peter
AU - Kox, Matthijs
AU - Beldman, Thijs J.
AU - Kluza, Ewelina
AU - van Leent, Mandy M. T.
AU - Teunissen, Abraham J. P.
AU - van der Meel, Roy
AU - Fayad, Zahi A.
AU - Joosten, Leo A. B.
AU - Fisher, Edward A.
AU - Merkx, Maarten
AU - Netea, Mihai G.
AU - Mulder, Willem J. M.
N1 - Funding Information: We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the β-glucan we used in our initial experiments. H. Lemmers (Radboudumc) kindly prepared the purified lipopolysaccharide used for stimulation of primary human monocytes and macrophages. Part of the figures were prepared using (among other software) Biorender.com. B.N. is supported by a National Health and Medical Research Council (Australia) Investigator Grant (APP1173314). This work was supported by National Institutes of Health grants R01 HL144072, R01 CA220234 and P01 HL131478, as well as a Vici grant from the Dutch Research Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N. was supported by a Spinoza grant from Dutch Research Council NWO and an ERC Advanced Grant (#833247). Funding Information: We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the β-glucan we used in our initial experiments. H. Lemmers (Radboudumc) kindly prepared the purified lipopolysaccharide used for stimulation of primary human monocytes and macrophages. Part of the figures were prepared using (among other software) Biorender.com. B.N. is supported by a National Health and Medical Research Council (Australia) Investigator Grant (APP1173314). This work was supported by National Institutes of Health grants R01 HL144072, R01 CA220234 and P01 HL131478, as well as a Vici grant from the Dutch Research Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N. was supported by a Spinoza grant from Dutch Research Council NWO and an ERC Advanced Grant (#833247). Publisher Copyright: © 2023, The Author(s).
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85161396285&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41551-023-01050-0
DO - https://doi.org/10.1038/s41551-023-01050-0
M3 - Article
C2 - 37291433
SN - 2157-846X
VL - 7
SP - 1097
EP - 1112
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 9
ER -