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 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

doi:10.1038/s41551-023-01050-0

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 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 PickkersMatthijs 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 (Corresponding author), Willem J M Mulder (Corresponding author)

Onderzoeksoutput: Bijdrage aan tijdschrift › Tijdschriftartikel › Academic › peer review

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1097-1112
Aantal pagina's	16
Tijdschrift	Nature Biomedical Engineering
Volume	7
Nummer van het tijdschrift	9
Vroegere onlinedatum	8 jun. 2023
DOI's	https://doi.org/10.1038/s41551-023-01050-0
Status	Gepubliceerd - 1 sep. 2023

Bibliografische nota

Financiering

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). 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).

Financiers	Financiernummer
Dutch National Research Council
National Institutes of Health, NIH	P01 HL131478, R01 CA220234, R01 HL144072
East Tennessee State University
European Research Council	833247
National Health and Medical Research Council	APP1173314

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Schrijver, D. P., Röring, R. J., Deckers, J., de Dreu, A., Toner, Y. C., Prevot, G., Priem, B., Munitz, J., Nugraha, E. G., van Elsas, Y., Azzun, A., Anbergen, T., Groh, L. A., Becker, A. M. D., Pérez-Medina, C., Oosterwijk, R. S., Novakovic, B., Moorlag, S. J. C. F. M., Jansen, A., ... Mulder, W. J. M. (2023). Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells. Nature Biomedical Engineering, 7(9), 1097-1112. https://doi.org/10.1038/s41551-023-01050-0

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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.",

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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 2023, 'Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells', Nature Biomedical Engineering, vol. 7, nr. 9, blz. 1097-1112. https://doi.org/10.1038/s41551-023-01050-0

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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

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AU - Novakovic, Boris

AU - Moorlag, Simone J C F M

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AU - Joosten, Leo A B

AU - Fisher, Edward A

AU - Merkx, Maarten

AU - Netea, Mihai G

AU - Mulder, Willem J M

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

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Financiering

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