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

Research output: Contribution to journal › Article › Academic › peer-review

54 Citations (Scopus)

115 Downloads (Pure)

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.

Original language	English
Pages (from-to)	1097-1112
Number of pages	16
Journal	Nature Biomedical Engineering
Volume	7
Issue number	9
Early online date	8 Jun 2023
DOIs	https://doi.org/10.1038/s41551-023-01050-0
Publication status	Published - 1 Sept 2023

Bibliographical note

Funding

We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the \u03B2-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).

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
National Institutes of Health	P01 HL131478, R01 CA220234, R01 HL144072
East Tennessee State University
European Union's Horizon 2020 - Research and Innovation Framework Programme	833247

Keywords

Animals
Humans
Interleukin-4/metabolism
Mice
Monocytes
Sepsis
Trained Immunity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, no. 9, pp. 1097-1112. https://doi.org/10.1038/s41551-023-01050-0

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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

PY - 2023/9/1

Y1 - 2023/9/1

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.

KW - Animals

KW - Humans

KW - Interleukin-4/metabolism

KW - Mice

KW - Monocytes

KW - Sepsis

KW - Trained Immunity

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DO - 10.1038/s41551-023-01050-0

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JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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