bims-mepmim 2023-07-23 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2023‒07‒23
eighteen papers selected by
Erika Mariana Palmieri
NIH/NCI Laboratory of Cancer ImmunoMetabolism

QUAS-R: An SLC1A5-mediated glutamine uptake assay with single-cell resolution reveals metabolic heterogeneity with immune populations.
Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.
IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer.
Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma.
How nearby nutrients shape tumor growth.
Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.
Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland.
Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils.
The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment.
Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth.
p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism.
An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression.
Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition.
S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons.
Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.
Cystathionine β-synthase (CBS) suppresses NLRP3 inflammasome activation via redox regulation in microglia.

Cell Rep. 2023 Jul 19. pii: S2211-1247(23)00839-2. [Epub ahead of print]42(8): 112828

QUAS-R: An SLC1A5-mediated glutamine uptake assay with single-cell resolution reveals metabolic heterogeneity with immune populations.

Leonard R Pelgrom, Gavin M Davis, Simon O'Shaughnessy, Emilie J M Wezenberg, Sander I Van Kasteren, David K Finlay, Linda V Sinclair.

  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.

Keywords:  CP: Immunology; CP: Metabolism; SLC1A5; amino acid transport; glutamine uptake; lymphocytes

DOI:  https://doi.org/10.1016/j.celrep.2023.112828
Nat Commun. 2023 Jul 20. 14(1): 4367

Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.

Shiqun Wang, Wei Yan, Lingkai Kong, Shuguang Zuo, Jingyi Wu, Chunxiao Zhu, Huaping Huang, Bohao He, Jie Dong, Jiwu Wei.

The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.

DOI: https://doi.org/10.1038/s41467-023-39683-z
Nat Commun. 2023 07 17. 14(1): 4251

IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer.

E Koncina, M Nurmik, V I Pozdeev, C Gilson, M Tsenkova, R Begaj, S Stang, A Gaigneaux, C Weindorfer, F Rodriguez, M Schmoetten, E Klein, J Karta, V S Atanasova, K Grzyb, P Ullmann, R Halder, M Hengstschläger, J Graas, V Augendre, Y E Karapetyan, L Kerger, N Zuegel, A Skupin, S Haan, J Meiser, H Dolznig, E Letellier.

Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.

DOI: https://doi.org/10.1038/s41467-023-39953-w
Cell Metab. 2023 Jul 14. pii: S1550-4131(23)00225-5. [Epub ahead of print]

Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.

Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver.

  Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.

Keywords:  brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil

DOI:  https://doi.org/10.1016/j.cmet.2023.06.015
J Hepatol. 2023 Jul 18. pii: S0168-8278(23)04984-X. [Epub ahead of print]

The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma.

Yijun Lu, Qikai Sun, Qifei Guan, Zechuan Zhang, Qifeng He, Jianbo He, Zetao Ji, Wenfang Tian, Xiaoliang Xu, Yang Liu, Yin Yin, Chang Zheng, Senlin Lian, Bing Xu, Pin Wang, Runqiu Jiang, Beicheng Sun.

  BACKGROUND & AIMS: Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear.METHODS: We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established DEN/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdhf/fLyz2cre) or Kupffer cells (Xdhf/fClec4fcre). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux.
RESULTS: We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment (TME), especially hypoxia. Using HCC-inflicted mice (Xdhf/fLyz2cre and Xdhf/fClec4fcre), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8+ T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of α-ketoglutarate (α-KG) was enhanced within XOR-depleted macrophages. XOR inhibited α-KG production by interacting with IDH3α catalytic sites (K142 and Q139). The increased IDH3α activity caused increased adenosine and kynurenic acid production in the TAMs, which enhanced the immunosuppressive effects of the TAMs and CD8+ T cells.
CONCLUSIONS: The XOR-IDH3α axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs.
IMPACT AND IMPLICATIONS: HCC is one of the cancers with the highest morbidity in the world, and its 5-year survival rate is low. Currently, lots of immunotherapies have been applied to the treatment of HCC, but the curative effects are not satisfactory. TME of HCC is full of different infiltrating immune cells. TAMs are vital components in TME and involved in HCC progression. Herein, we confirm the downregulation of XOR expression in TAMs isolated from human HCC tissues. The loss of XOR in monocyte-derived macrophages increases IDH3 activity and results in an increase in α-KG production, which can promote M2-like polarization. Additionally, XOR-null TAMs derived from monocytes promote CD8+ T-cell exhaustion via the upregulation of immunosuppressive metabolites, including adenosine and KYNA. Given the prevalence and high rate of incidence of HCC and the need for improved therapeutic options for patients, our findings identify potential therapeutic targets that may be further studied to develop improved therapies.

Keywords:  Tumor-associated macrophages; hepatocellular carcinoma; immunotherapy; isocitrate dehydrogenase 3α; xanthine oxidoreductase

DOI:  https://doi.org/10.1016/j.jhep.2023.06.022
Elife. 2023 07 17. pii: e89825. [Epub ahead of print]12

How nearby nutrients shape tumor growth.

Nada Kalaany.

  Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.

Keywords:  amino acid homeostasis; biochemistry; cancer; cancer biology; chemical biology; human; immunotherapy; metabolism; mouse; nutrient stress; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.89825
Nat Metab. 2023 Jul 17.

Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

Brenda Morant-Ferrando, Daniel Jimenez-Blasco, Paula Alonso-Batan, Jesús Agulla, Rebeca Lapresa, Dario Garcia-Rodriguez, Sara Yunta-Sanchez, Irene Lopez-Fabuel, Emilio Fernandez, Peter Carmeliet, Angeles Almeida, Marina Garcia-Macia, Juan P Bolaños.

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses1,2. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic3-7, suggesting glucose is their main metabolic precursor. Notably, transcriptomic data8,9 and in vitro10 studies reveal that mouse astrocytes are capable of mitochondrially oxidizing fatty acids and that they can detoxify excess neuronal-derived fatty acids in disease models11,12. Still, the factual metabolic advantage of fatty acid use by astrocytes and its physiological impact on higher-order cerebral functions remain unknown. Here, we show that knockout of carnitine-palmitoyl transferase-1A (CPT1A)-a key enzyme of mitochondrial fatty acid oxidation-in adult mouse astrocytes causes cognitive impairment. Mechanistically, decreased fatty acid oxidation rewired astrocytic pyruvate metabolism to facilitate electron flux through a super-assembled mitochondrial respiratory chain, resulting in attenuation of reactive oxygen species formation. Thus, astrocytes naturally metabolize fatty acids to preserve the mitochondrial respiratory chain in an energetically inefficient disassembled conformation that secures signalling reactive oxygen species and sustains cognitive performance.

DOI: https://doi.org/10.1038/s42255-023-00835-6
Sci Adv. 2023 Jul 21. 9(29): eadf6710

Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland.

Anke Witt, Ivona Mateska, Alessandra Palladini, Anupam Sinha, Michele Wölk, Akiko Harauma, Nicole Bechmann, Christina Pamporaki, Andreas Dahl, Michael Rothe, Irakli Kopaliani, Christian Adolf, Anna Riester, Ben Wielockx, Stefan R Bornstein, Matthias Kroiss, Mirko Peitzsch, Toru Moriguchi, Maria Fedorova, Michal Grzybek, Triantafyllos Chavakis, Peter Mirtschink, Vasileia Ismini Alexaki.

Corticosteroids regulate vital processes, including stress responses, systemic metabolism, and blood pressure. Here, we show that corticosteroid synthesis is related to the polyunsaturated fatty acid (PUFA) content of mitochondrial phospholipids in adrenocortical cells. Inhibition of the rate-limiting enzyme of PUFA synthesis, fatty acid desaturase 2 (FADS2), leads to perturbations in the mitochondrial lipidome and diminishes steroidogenesis. Consistently, the adrenocortical mitochondria of Fads2-/- mice fed a diet with low PUFA concentration are structurally impaired and corticoid levels are decreased. On the contrary, FADS2 expression is elevated in the adrenal cortex of obese mice, and plasma corticosterone is increased, which can be counteracted by dietary supplementation with the FADS2 inhibitor SC-26192 or icosapent ethyl, an eicosapentaenoic acid ethyl ester. In humans, FADS2 expression is elevated in aldosterone-producing adenomas compared to non-active adenomas or nontumorous adrenocortical tissue and correlates with expression of steroidogenic genes. Our data demonstrate that FADS2-mediated PUFA synthesis determines adrenocortical steroidogenesis in health and disease.

DOI: https://doi.org/10.1126/sciadv.adf6710
Nat Commun. 2023 07 19. 14(1): 4356

Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.

Luis Rios, Suman Pokhrel, Sin-Jin Li, Gwangbeom Heo, Bereketeab Haileselassie, Daria Mochly-Rosen.

The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.

DOI: https://doi.org/10.1038/s41467-023-40043-0
Nat Commun. 2023 07 17. 14(1): 4280

The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils.

Juliana Escher Toller-Kawahisa, Carlos Hiroji Hiroki, Camila Meirelles de Souza Silva, Daniele Carvalho Nascimento, Gabriel Azevedo Públio, Timna Varela Martins, Luis Eduardo Alves Damasceno, Flávio Protásio Veras, Paula Ramos Viacava, Fábio Yuji Sukesada, Emily Anne Day, Alessia Zotta, Tristram Alexander Jasper Ryan, Rodrigo Moreira da Silva, Thiago Mattar Cunha, Norberto Peporine Lopes, Fernando de Queiroz Cunha, Luke Anthony John O'Neill, José Carlos Alves-Filho.

Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2 (PKM2) is a glycolytic enzyme known to be involved in metabolic reprogramming and gene transcription in many immune cell types, its role in neutrophils remains poorly understood. Here, we report that PKM2 regulates ROS production and microbial killing by neutrophils. Zymosan-activated neutrophils showed increased cytoplasmic expression of PKM2. Pharmacological inhibition or genetic deficiency of PKM2 in neutrophils reduced ROS production and Staphylococcus aureus killing in vitro. In addition, this also resulted in phosphoenolpyruvate (PEP) accumulation and decreased dihydroxyacetone phosphate (DHAP) production, which is required for de novo synthesis of diacylglycerol (DAG) from glycolysis. In vivo, PKM2 deficiency in myeloid cells impaired the control of infection with Staphylococcus aureus. Our results fill the gap in the current knowledge of the importance of lower glycolysis for ROS production in neutrophils, highlighting the role of PKM2 in regulating the DHAP and DAG synthesis to promote ROS production in neutrophils.

DOI: https://doi.org/10.1038/s41467-023-40021-6
Am J Physiol Cell Physiol. 2023 Jul 17.

The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment.

Giuseppe Taurino, Martina Chiu, Massimiliano G Bianchi, Erika Griffini, Ovidio Bussolati.

  SLC38A5/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na+ (symport) and H+ (antiport). Its preferential substrates are amino acids with side chains containing amide (glutamine, and asparagine) or imidazole (histidine) groups, but also serine, glycine and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/β-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. We review the functional role of the SNAT5 transporter in pathophysiology and propose that, due to its peculiar operational and regulatory features, SNAT5 may play important pro-cancer roles when expressed either in neoplastic or in stromal cells of glutamine-auxotroph tumors.

Keywords:  Amino acid transport; Asparagine; Cancer; Glutamine; Metabolic diseases

DOI:  https://doi.org/10.1152/ajpcell.00169.2023
J Clin Invest. 2023 Jul 20. pii: e164599. [Epub ahead of print]

Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth.

Matthew D Taves, Shizuka Otsuka, Michaela A Taylor, Kaitlynn M Donahue, Thomas J Meyer, Margaret C Cam, Jonathan D Ashwell.

  Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-HSD1 (encoded by Hsd11b1). Here we find that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth but reduced in vivo tumor progression, which corresponded with increased frequencies of tumor-infiltrating CD8+ T cells (TIL) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of Tconv activation in tumor-infiltrating Treg. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11β-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.

Keywords:  Adaptive immunity; Cancer; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI164599
Nat Commun. 2023 Jul 21. 14(1): 4403

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism.

Jonuelle Acosta, Qinglan Li, Nelson F Freeburg, Nivitha Murali, Alexandra Indeglia, Grant P Grothusen, Michelle Cicchini, Hung Mai, Amy C Gladstein, Keren M Adler, Katherine R Doerig, Jinyang Li, Miguel Ruiz-Torres, Kimberly L Manning, Ben Z Stanger, Luca Busino, Maureen Murphy, Liling Wan, David M Feldser.

The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

DOI: https://doi.org/10.1038/s41467-023-40161-9
Immunity. 2023 Jul 13. pii: S1074-7613(23)00269-8. [Epub ahead of print]

An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression.

Qiong Luo, Yijun Liu, Ke Shi, Xuecheng Shen, Yaqi Yang, Xuejiao Liang, Liangliang Lu, Wenxuan Qiao, Airu Chen, Dongmei Hong, Yang Sun, Qiang Xu.

  Anti-interleukin-17 (IL-17) therapy has been used in various autoimmune diseases. However, the efficacy is unexpectedly limited in several IL-17-associated diseases, and the mechanism of limited efficacy remains unclear. Here, we show that a molecular complex containing the adaptor molecule Act1 and tyrosine phosphatase SHP2 mediated autonomous IL-17R signaling that accelerated and sustained inflammation. SHP2, aberrantly augmented in various autoimmune diseases, was induced by IL-17A itself in astrocytes and keratinocytes, sustaining chemokine production even upon anti-IL-17 therapies. Mechanistically, SHP2 directly interacted with and dephosphorylated Act1, which replaced Act1-TRAF5 complexes and induced IL-17-independent activation of IL-17R signaling. Genetic or pharmacologic inactivation of SHP2, or blocking Act1-SHP2 interaction, paralyzed both IL-17-induced and IL-17-independent signaling and attenuated primary or relapsing experimental autoimmune encephalomyelitis. Therefore, Act1-SHP2 complexes mediate an alternative pathway for autonomous activation of IL-17R signaling, targeting which could be a therapeutic option for IL-17-related diseases in addition to current antibody therapies.

Keywords:  Act1; IL-17-related autoimmune diseases; IL-17R signaling; SHP2; dephosphorylation

DOI:  https://doi.org/10.1016/j.immuni.2023.06.012
J Clin Invest. 2023 Jul 18. pii: e171267. [Epub ahead of print]

Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition.

Cheen Fei Chin, Dwight LA Galam, Liang Gao, Bryan C Tan, Bernice H Wong, Geok-Lin Chua, Randy Y J Loke, Yen Ching Lim, Markus R Wenk, Miao Shan Lim, Wei-Qiang Leow, George Bb Goh, Federico Torta, David L Silver.

  The liver has a high demand for phosphatidylcholine (PC) particularly in overnutrition where reduced phospholipid levels have been implicated in the development of non-alcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter Mfsd2a as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust NASH-like phenotype within just two weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFA). Treating hepatocytes with LPC containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid DHA promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA containing LPCs drive both hepatic lipid droplet formation, suppress lipogenesis and sustain hepatic phospholipid pools--processes that are critical for protecting the liver from excess dietary fat.

Keywords:  Hepatology; Homeostasis; Metabolism; Mouse models; Transport

DOI:  https://doi.org/10.1172/JCI171267
Cell Chem Biol. 2023 Jul 04. pii: S2451-9456(23)00196-4. [Epub ahead of print]

S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons.

Paschalis-Thomas Doulias, Hongmei Yang, Alexander Y Andreyev, Nima Dolatabadi, Henry Scott, Charlene K Raspur, Parth R Patel, Tomohiro Nakamura, Steven R Tannenbaum, Harry Ischiropoulos, Stuart A Lipton.

A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.

DOI: https://doi.org/10.1016/j.chembiol.2023.06.018
Cell Rep. 2023 Jul 19. pii: S2211-1247(23)00774-X. [Epub ahead of print]42(8): 112763

Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Alastair J Hayes, Xiaozhong Zheng, James O'Kelly, Lucile P A Neyton, Natalia A Bochkina, Iain Uings, John Liddle, J Kenneth Baillie, George Just, Margaret Binnie, Natalie Z M Homer, Toby B J Murray, James Baily, Kris McGuire, Christos Skouras, O James Garden, Scott P Webster, John P Iredale, Sarah E M Howie, Damian J Mole.

  Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Keywords:  3-hydroxykynurenine; CP: Metabolism; acute pancreatitis; critical illness; kynurenine 3-monooxygenase; metabolomics; multiple organ failure; transcriptome

DOI:  https://doi.org/10.1016/j.celrep.2023.112763
Antioxid Redox Signal. 2023 Jul 18.

Cystathionine β-synthase (CBS) suppresses NLRP3 inflammasome activation via redox regulation in microglia.

Yu-Jie Mou, Ya-Ting Ma, Xin Yuan, Miao Wang, Yang Liu, Chong-Shuang Pei, Chun-Feng Liu, Xiao-Ou Hou, Lifang Hu.

AIMS: Cystathionine β-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H2S), glutathione (GSH) and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H2S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects NLRP3 inflammasome activity and other pathologies in PD.RESULTS: Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H2S generation were found in the brains of microglial cbs conditional knockout (cbscKO) mice, while serum and brain Hcy levels remained unaltered. Moreover, microglial cbscKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas CBS overexpression or activation produced opposite effects. In vitro studies showed that CBS overexpression or activation suppressed microglial NLRP3 inflammasome activation and IL-1β secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of cbs enhanced NLRP3 expression and mitoROS generation, and augmented microglial NLRP3 inflammasome activity in response to ATP challenge, which was blocked by the mitoROS scavenger.
INNOVATION AND CONCLUSIONS: The study demonstrated an elevated GSSG level and reduced H2S generation, which correlated with a susceptible status of microglia in the brain of cbscKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.

DOI: https://doi.org/10.1089/ars.2022.0174