AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.

Autor:	Brombacher EC; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands., Patente TA; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands., van der Ham AJ; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands., Moll TJA; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands., Otto F; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands., Verheijen FWM; Department Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands., Zaal EA; Department Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands., de Ru AH; Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden, Netherlands., Tjokrodirijo RTN; Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden, Netherlands., Berkers CR; Department Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands., van Veelen PA; Center for Proteomics and Metabolomics, Leiden University Medical Center , Leiden, Netherlands., Guigas B; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands., Everts B; Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2024 Oct 07; Vol. 223 (10). Date of Electronic Publication: 2024 Aug 08.
DOI:	10.1083/jcb.202401024
Abstrakt:	Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings. (© 2024 Brombacher et al.)
Databáze:	MEDLINE
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