Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
21
12
2021
accepted:
02
05
2023
medline:
18
9
2023
pubmed:
9
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37291433
doi: 10.1038/s41551-023-01050-0
pii: 10.1038/s41551-023-01050-0
pmc: PMC10504080
doi:
Substances chimiques
Interleukin-4
207137-56-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1097-1112Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL131478
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220234
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144072
Pays : United States
Informations de copyright
© 2023. The Author(s).
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