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1.
iScience ; 27(6): 109940, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38832024

RESUMEN

SARM1 is a Toll-IL-1 receptor (TIR) domain-containing protein with roles in innate immunity and neuronal death in diverse organisms. Unlike other innate immune TIR proteins that function as adaptors for Toll-like receptors (TLRs), SARM1 has NADase activity, and this activity regulates murine neuronal cell death. However, whether human SARM1, and its NADase activity, are involved in innate immune regulation remains unclear. Here, we show that human SARM1 regulates proinflammatory cytokine expression in both an NADase-dependent and -independent manner in monocytes. SARM1 negatively regulated TLR4-dependent TNF mRNA induction independently of its NADase activity. In contrast, SARM1 inhibited IL-1ß secretion through both NADase-dependent inhibition of pro-IL-1ß expression, and NADase-independent suppression of the NLRP3 inflammasome and hence processing of pro-IL-1ß to mature IL-1ß. Our study reveals multiple mechanisms whereby SARM1 regulates pro-inflammatory cytokines in human monocytes and shows, compared to other mammalian TIR proteins, a distinct NADase-dependent role for SARM1 in innate immunity.

2.
J Biol Chem ; 300(2): 105620, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38176648

RESUMEN

Sterile alpha and HEAT/armadillo motif-containing protein (SARM1) was recently described as a NAD+-consuming enzyme and has previously been shown to regulate immune responses in macrophages. Neuronal SARM1 is known to contribute to axon degeneration due to its NADase activity. However, how SARM1 affects macrophage metabolism has not been explored. Here, we show that macrophages from Sarm1-/- mice display elevated NAD+ concentrations and lower cyclic ADP-ribose, a known product of SARM1-dependent NAD+ catabolism. Further, SARM1-deficient macrophages showed an increase in the reserve capacity of oxidative phosphorylation and glycolysis compared to WT cells. Stimulation of macrophages to a proinflammatory state by lipopolysaccharide (LPS) revealed that SARM1 restricts the ability of macrophages to upregulate glycolysis and limits the expression of the proinflammatory gene interleukin (Il) 1b, but boosts expression of anti-inflammatory Il10. In contrast, we show macrophages lacking SARM1 induced to an anti-inflammatory state by IL-4 stimulation display increased oxidative phosphorylation and glycolysis, and reduced expression of the anti-inflammatory gene, Fizz1. Overall, these data show that SARM1 fine-tunes immune gene transcription in macrophages via consumption of NAD+ and altered macrophage metabolism.


Asunto(s)
Proteínas del Dominio Armadillo , Proteínas del Citoesqueleto , Neuronas , Animales , Ratones , Proteínas del Dominio Armadillo/genética , Proteínas del Dominio Armadillo/metabolismo , Axones/metabolismo , ADP-Ribosa Cíclica/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , NAD/metabolismo , Neuronas/metabolismo
3.
Cell Rep ; 42(8): 112828, 2023 08 29.
Artículo en Inglés | MEDLINE | ID: mdl-37478011

RESUMEN

System-level analysis of single-cell data is rapidly transforming the field of immunometabolism. Given the competitive demand for nutrients in immune microenvironments, there is a need to understand how and when immune cells access these nutrients. Here, we describe a new approach for single-cell analysis of nutrient uptake where we use in-cell biorthogonal labeling of a functionalized amino acid after transport into the cell. In this manner, the bona fide active uptake of glutamine via SLC1A5/ASCT2 could be quantified. We used this assay to interrogate the transport capacity of complex immune subpopulations, both in vitro and in vivo. Taken together, our findings provide an easy sensitive single-cell assay to assess which cells support their function via SLC1A5-mediated uptake. This is a significant addition to the single-cell metabolic toolbox required to decode the metabolic landscape of complex immune microenvironments.


Asunto(s)
Aminoácidos , Glutamina , Glutamina/metabolismo , Línea Celular Tumoral , Proliferación Celular , Transporte Biológico , Aminoácidos/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo
4.
Nat Commun ; 12(1): 1460, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674584

RESUMEN

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1ß in vitro. Accordingly, HIF-1α and IL-1ß are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2-/- mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.


Asunto(s)
Arginasa/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Mitocondrias/metabolismo , Animales , Arginasa/genética , Regulación hacia Abajo , Femenino , Interleucina-1beta/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Mitocondrias/enzimología , Succinato Deshidrogenasa/metabolismo
5.
Front Mol Neurosci ; 12: 219, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31619961

RESUMEN

Mitochondrial dysfunction is a recognized hallmark of neurodegenerative diseases and abnormal mitochondrial fusion-fission dynamics have been implicated in the pathogenesis of neurodegenerative disorders. This study characterizes the effects of metabolic flux inhibitors and activators on mitochondrial fusion dynamics in the neuronal cell culture model of differentiated PC12 cells. Using a real time confocal microscopy assay, it was found that the carnitine palmitoyltransferase I (CPTI) inhibitor, etomoxir, reduced mitochondrial fusion dynamics in a time-dependent manner. Etomoxir also decreased JO2, ΔΨm and reactive oxygen species (ROS) production rates. The mitochondrial pyruvate carrier (MPC) inhibitor, UK5099, reduced fusion dynamics and in combination with etomoxir these inhibitory effects were amplified. Use of the pyruvate dehydrogenase (PDH) kinase inhibitor dichloroacetate, which is known to increase metabolic flux through PDH, reversed the etomoxir-induced effects on fusion dynamics, JO2, ΔΨm but not ROS production rates. Dichloroacetate also partially reversed inhibition of mitochondrial fusion dynamics caused by the parkinsonian-inducing neurotoxin, MPP+. These results suggest that dichloroacetate-induced activation of metabolic flux in the mitochondrion may be a mechanism to restore normal mitochondrial fusion-fission dynamics in metabolically challenged cells.

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