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1.
Mol Cell ; 84(4): 744-759.e6, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38266638

ABSTRACT

Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1ß production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1ß expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1ß maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1ß production, providing a potential inflammatory disease target.


Subject(s)
NAD , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Mice , Acetylation , Epigenesis, Genetic , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Macrophages/metabolism , NAD/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Protein Processing, Post-Translational , Serine/metabolism
2.
Trends Endocrinol Metab ; 35(1): 62-73, 2024 01.
Article in English | MEDLINE | ID: mdl-37778898

ABSTRACT

Carbon metabolism, including one-carbon (1C) metabolism and central carbon metabolism (CCM), provides energy for the cell and generates metabolites with signaling activities. The regulation of macrophage polarization involves complex signals and includes an epigenetic level. Epigenetic modifications through changes in carbon metabolism allow macrophages to respond in a timely manner to their environment and adapt to metabolic demands during macrophage polarization. Here we summarize the current understanding of the crosstalk between carbon metabolism and epigenetic modifications in macrophages under physiological conditions and in the tumor microenvironment (TME) and provide targets and further directions for macrophage-associated diseases.


Subject(s)
Macrophages , Signal Transduction , Humans , Macrophages/metabolism , Epigenesis, Genetic
3.
Sci Adv ; 10(20): eadn2867, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38758794

ABSTRACT

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.


Subject(s)
Macrophages , Mitochondria , Organelle Biogenesis , Phosphoglycerate Dehydrogenase , Reactive Oxygen Species , Serine , Macrophages/metabolism , Animals , Mitochondria/metabolism , Phosphoglycerate Dehydrogenase/metabolism , Phosphoglycerate Dehydrogenase/genetics , Serine/metabolism , Mice , Reactive Oxygen Species/metabolism , Signal Transduction , Mice, Knockout , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Inflammation/metabolism , Inflammation/pathology , Obesity/metabolism , Obesity/pathology , Obesity/genetics , Mice, Inbred C57BL
4.
Sci Bull (Beijing) ; 69(15): 2405-2419, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38614854

ABSTRACT

Excitatory amino acid transporters (EAATs) are responsible for excitatory amino acid transportation and are associated with auto-immune diseases in the central nervous system and peripheral tissues. However, the subcellular location and function of EAAT2 in macrophages are still obscure. In this study, we demonstrated that LPS stimulation increases expression of EAAT2 (coded by Slc1a2) via NF-κB signaling. EAAT2 is necessary for inflammatory macrophage polarization through sustaining mTORC1 activation. Mechanistically, lysosomal EAAT2 mediates lysosomal glutamate and aspartate efflux to maintain V-ATPase activation, which sustains macropinocytosis and mTORC1. We also found that mice with myeloid depletion of Slc1a2 show alleviated inflammatory responses in LPS-induced systemic inflammation and high-fat diet induced obesity. Notably, patients with type II diabetes (T2D) have a higher level of expression of lysosomal EAAT2 and activation of mTORC1 in blood macrophages. Taken together, our study links the subcellular location of amino acid transporters with the fate decision of immune cells, which provides potential therapeutic targets for the treatment of inflammatory diseases.


Subject(s)
Excitatory Amino Acid Transporter 2 , Inflammation , Lysosomes , Macrophages , Mechanistic Target of Rapamycin Complex 1 , Animals , Macrophages/metabolism , Macrophages/immunology , Macrophages/drug effects , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Excitatory Amino Acid Transporter 2/metabolism , Excitatory Amino Acid Transporter 2/genetics , Lysosomes/metabolism , Inflammation/metabolism , Inflammation/immunology , Humans , Lipopolysaccharides/pharmacology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/immunology , Glutamic Acid/metabolism , Mice, Inbred C57BL , NF-kappa B/metabolism , Aspartic Acid/metabolism , Male , Obesity/metabolism , Obesity/immunology , Signal Transduction , Diet, High-Fat/adverse effects , Pinocytosis/drug effects
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