bims-imicid 2024-01-28 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒01‒28
35 papers selected by
Dylan Ryan, University of Cambridge

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.
Inosine induces stemness features in CAR-T cells and enhances potency.
Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation.
Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
Sulfated bile acid is a host-derived ligand for MAIT cells.
NF-κB RelA is a cell-intrinsic metabolic checkpoint restricting glycolysis.
Interleukin-21 Drives a Hypermetabolic State and CD4+ T Cell-associated Pathogenicity in Chronic Intestinal Inflammation.
Metabolic Enzymes in Viral Infection and Host Innate Immunity.
Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.
Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs.
EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
Immunometabolism, extracellular vesicles and cardiac injury.
A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism.
Inflammaging and fatty acid oxidation in monocytes and macrophages.
Metabolic reprogramming of immune cells by mitochondrial division inhibitor-1 to prevent post-vascular injury neointimal hyperplasia.
Melatonin: a modulator in metabolic rewiring in T-cell malignancies.
Altered metabolism and DAM-signatures in female brains and microglia with aging.
New sights of immunometabolism and agent progress in colitis associated colorectal cancer.
Deciphering metabolic crosstalk in context: lessons from inflammatory diseases.
Integrated Bulk and Single-Cell RNA-Sequencing Reveals the Effects of Circadian Rhythm Disruption on the Metabolic Reprogramming of CD4+ T Cells in Alzheimer's Disease.
The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization.
One carbon metabolism and its implication in health and immune functions.
Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.
Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
Reduced mitochondrial respiration in peripheral T cells after paediatric heamatopoietic stem cell transplantation.
Inhibition of pseudorabies virus replication via upregulated interferon response by targeting 7-dehydrocholesterol reductase.
Take my breath away-mitochondrial dysfunction drives CD8+ T cell exhaustion.
HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells.
Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of hepatic stellate cells.
Influenza A virus selectively elevates prostaglandin E2 formation in pro-resolving macrophages.
LPCAT1 facilitates keratinocyte hyperproliferation and skin inflammation in psoriasis via regulating GLUT3.
Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.
Mitochondrial translocation of TFEB regulates complex I and inflammation.
Activation of murine macrophages by membrane proteins from Tritrichomonas foetus grown on iron- and calcium-rich conditions.

Cell Rep. 2024 Jan 23. pii: S2211-1247(24)00028-7. [Epub ahead of print]43(2): 113700

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.

Milton Pereira, Jonathan Liang, Joy Edwards-Hicks, Allison M Meadows, Christine Hinz, Sonia Liggi, Matthias Hepprich, Jonathan Mudry, Kim Han, Julian L Griffin, Iain Fraser, Michael N Sack, Christoph Hess, Clare E Bryant.

  Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

Keywords:  CP: Immunology; CP: Metabolism; NLRP3; eicosanoids; inflammasome; inflammation; lipidomics; metaflammation; prostaglandins

DOI:  https://doi.org/10.1016/j.celrep.2024.113700
Cancer Cell. 2024 Jan 17. pii: S1535-6108(24)00008-4. [Epub ahead of print]

Inosine induces stemness features in CAR-T cells and enhances potency.

Dorota D Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A Freitas, Yiyun Chen, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Vimal Keerthi, Amaury Leruste, Malek Bashti, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L Davis, Ansuman T Satpathy, Steven A Feldman, Elena Sotillo, Crystal L Mackall.

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.

DOI: https://doi.org/10.1016/j.ccell.2024.01.002
Mol Cell. 2024 Jan 17. pii: S1097-2765(24)00003-0. [Epub ahead of print]

Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation.

Chuanlong Wang, Qingyi Chen, Siyuan Chen, Lijuan Fan, Zhending Gan, Muyang Zhao, Lexuan Shi, Peng Bin, Guan Yang, Xihong Zhou, Wenkai Ren.

  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)-1β production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1β expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1β 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-1β production, providing a potential inflammatory disease target.

Keywords:  NAD(+); NLRP3; PHGDH; SIRT1; SIRT3; TLR4; acetylation; macrophage; serine

DOI:  https://doi.org/10.1016/j.molcel.2024.01.002
Nat Immunol. 2024 Jan 23.

Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.

Jingwei Ma, Liang Tang, Yaoyao Tan, Jingxuan Xiao, Keke Wei, Xin Zhang, Yuan Ma, Shuai Tong, Jie Chen, Nannan Zhou, Li Yang, Zhang Lei, Yonggang Li, Jiadi Lv, Junwei Liu, Huafeng Zhang, Ke Tang, Yi Zhang, Bo Huang.

The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

DOI: https://doi.org/10.1038/s41590-023-01738-0
Sci Immunol. 2024 Jan 26. 9(91): eade6924

Sulfated bile acid is a host-derived ligand for MAIT cells.

Emi Ito, Shinsuke Inuki, Yoshihiro Izumi, Masatomo Takahashi, Yuki Dambayashi, Lisa Ciacchi, Wael Awad, Ami Takeyama, Kensuke Shibata, Shotaro Mori, Jeffrey Y W Mak, David P Fairlie, Takeshi Bamba, Eri Ishikawa, Masamichi Nagae, Jamie Rossjohn, Sho Yamasaki.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin-based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue-derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes (Sult2a1-8) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.

DOI: https://doi.org/10.1126/sciimmunol.ade6924
Cell Biosci. 2024 Jan 20. 14(1): 11

NF-κB RelA is a cell-intrinsic metabolic checkpoint restricting glycolysis.

Liwen Li, Lei Han, Zhaoxia Qu.

  An intrinsic link between metabolism and function in immune cells, and in particular macrophages, has been well established recently. However, the molecular mechanisms controlling the metabolic switch in these sentinel cells for their integral roles in host defense, inflammation, homeostasis, and pathogenesis remain largely unknown. Here, we identify the master transcription factor NF-κB RelA as a vital cell-intrinsic checkpoint restricting aerobic glycolysis to favor mitochondrial oxidative phosphorylation (OXPHOS) and "M2" activation (alternative anti-inflammatory and pro-tumorigenic activation, in contrast to classical pro-inflammatory and anti-tumor M1 activation) of macrophages under oncogenic stress. RelA specific knockdown or genetic deletion in macrophages causes metabolism to shift away from OXPHOS toward glycolysis, resulting in drastically decreased oxygen consumption but significantly increased lactate and ATP production. The metabolic change in RelA deficient cells is associated with the decrease in the expressions of the OXPHOS gene SCO2 as well as the M2 marker and function genes arginase-1 and VEGF. These data suggest that RelA induces SCO2 expression to enhance OXPHOS and restrict glycolysis in macrophages for their pro-tumorigenic activation.

Keywords:  Glycolysis; Macrophages; Metabolic checkpoint; Metabolic switch; Metabolism; NF-κB; Oxidative phosphorylation; RelA/p65

DOI:  https://doi.org/10.1186/s13578-024-01196-7
Gastroenterology. 2024 Jan 22. pii: S0016-5085(24)00063-5. [Epub ahead of print]

Interleukin-21 Drives a Hypermetabolic State and CD4+ T Cell-associated Pathogenicity in Chronic Intestinal Inflammation.

Adebowale O Bamidele, Shravan K Mishra, Guilherme Piovezani Ramos, Petra Hirsova, Emily E Klatt, Leena M Abdelrahman, Mary R Sagstetter, Heidi M Davidson, Patrick J Fehrenbach, Lucia Valenzuela-Pérez, Hyun Se Kim Lee, Song Zhang, Abner Aguirre Lopez, Ahmed T Kurdi, Maria S Westphal, Michelle M Gonzalez, Joseph M Gaballa, Robyn Laura Kosinsky, Hee Eun Lee, Thomas C Smyrk, Glenn Bantug, Naomi M Gades, William A Faubion.

  BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease (IBD); however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis.METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing Seahorse XF analyzer. We utilized Crohn's disease single-cell RNA sequencing dataset to infer therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically-modified Tregs in CD4+ T cell-induced murine colitis models.
RESULTS: Mitochondria-endoplasmic reticulum (ER) appositions, known to mediate pyruvate entry into mitochondria via VDAC1, are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate (MePyr) supplementation. Notably, IL-21 diminished mitochondria-ER appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β (GSK3β), a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. MePyr and GSK3β pharmacologic inhibitor (LY2090314) reversed IL-21-induced metabolic rewiring and inflammatory state. Moreover, IL-21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs.
CONCLUSIONS: IL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4+ T cell-driven chronic intestinal inflammation.

Keywords:  Inflammatory Bowel Disease; Interleukins; Mitochondria-ER appositions; Pyruvate; Regulatory T cells

DOI:  https://doi.org/10.1053/j.gastro.2024.01.026
Viruses. 2023 Dec 24. pii: 35. [Epub ahead of print]16(1):

Metabolic Enzymes in Viral Infection and Host Innate Immunity.

Chao Qin, Taolin Xie, Wayne Wei Yeh, Ali Can Savas, Pinghui Feng.

  Metabolic enzymes are central players for cell metabolism and cell proliferation. These enzymes perform distinct functions in various cellular processes, such as cell metabolism and immune defense. Because viral infections inevitably trigger host immune activation, viruses have evolved diverse strategies to blunt or exploit the host immune response to enable viral replication. Meanwhile, viruses hijack key cellular metabolic enzymes to reprogram metabolism, which generates the necessary biomolecules for viral replication. An emerging theme arising from the metabolic studies of viral infection is that metabolic enzymes are key players of immune response and, conversely, immune components regulate cellular metabolism, revealing unexpected communication between these two fundamental processes that are otherwise disjointed. This review aims to summarize our present comprehension of the involvement of metabolic enzymes in viral infections and host immunity and to provide insights for potential antiviral therapy targeting metabolic enzymes.

Keywords:  antiviral therapy; cell metabolism; inflammatory response; innate immunity; interferon; metabolic enzymes; viral infection

DOI:  https://doi.org/10.3390/v16010035
Cell Death Discov. 2024 Jan 20. 10(1): 39

Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.

Sheng Zhang, Kebing Lv, Zhen Liu, Ran Zhao, Fei Li.

Metabolic competition between tumour cells and immune cells for limited nutrients is an important feature of the tumour microenvironment (TME) and is closely related to the outcome of tumour immune escape. A large number of studies have proven that tumour cells need metabolic reprogramming to cope with acidification and hypoxia in the TME while increasing energy uptake to support their survival. Among them, synthesis, oxidation and uptake of fatty acids (FAs) in the TME are important manifestations of lipid metabolic adaptation. Although different immune cell subsets often show different metabolic characteristics, various immune cell functions are closely related to fatty acids, including providing energy, providing synthetic materials and transmitting signals. In the face of the current situation of poor therapeutic effects of tumour immunotherapy, combined application of targeted immune cell fatty acid metabolism seems to have good therapeutic potential, which is blocked at immune checkpoints. Combined application of adoptive cell therapy and cancer vaccines is reflected. Therefore, it is of great interest to explore the role of fatty acid metabolism in immune cells to discover new strategies for tumour immunotherapy and improve anti-tumour immunity.

DOI: https://doi.org/10.1038/s41420-024-01807-9
Nat Commun. 2024 Jan 23. 15(1): 686

AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.

Taiqi Chen, Siyi Xie, Jie Cheng, Qiao Zhao, Hong Wu, Peng Jiang, Wenjing Du.

Many types of tumors feature aerobic glycolysis for meeting their increased energetic and biosynthetic demands. However, it remains still unclear how this glycolytic phenomenon is achieved and coordinated with other metabolic pathways in tumor cells in response to growth stimuli. Here we report that activation of AKT1 induces a metabolic switch to glycolysis from the mitochondrial metabolism via phosphorylation of cytoplasmic malic enzyme 2 (ME2), named ME2fl (fl means full length), favoring an enhanced glycolytic phenotype. Mechanistically, in the cytoplasm, AKT1 phosphorylates ME2fl at serine 9 in the mitochondrial localization signal peptide at the N-terminus, preventing its mitochondrial translocation. Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as Lactate dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, AKT1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by AKT1 in the metabolic adaptation of tumor cells to growth stimuli.

DOI: https://doi.org/10.1038/s41467-024-44772-8
Int J Mol Sci. 2024 Jan 13. pii: 996. [Epub ahead of print]25(2):

Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs.

Qingqing Liu, Xiaoyu Yan, Runyuan Li, Yuan Yuan, Jian Wang, Yuanxin Zhao, Jiaying Fu, Jing Su.

  Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and, with increasing research on the tumor immune microenvironment (TIME), the immunosuppressive micro-environment of HCC hampers further application of immunotherapy, even though immunotherapy can provide survival benefits to patients with advanced liver cancer. Current studies suggest that polyamine metabolism is not only a key metabolic pathway for the formation of immunosuppressive phenotypes in tumor-associated macrophages (TAMs), but it is also profoundly involved in mitochondrial quality control signaling and the energy metabolism regulation process, so it is particularly important to further investigate the role of polyamine metabolism in the tumor microenvironment (TME). In this review, by summarizing the current research progress of key enzymes and substrates of the polyamine metabolic pathway in regulating TAMs and T cells, we propose that polyamine biosynthesis can intervene in the process of mitochondrial energy metabolism by affecting mitochondrial autophagy, which, in turn, regulates macrophage polarization and T cell differentiation. Polyamine metabolism may be a key target for the interactive dialog between HCC cells and immune cells such as TAMs, so interfering with polyamine metabolism may become an important entry point to break intercellular communication, providing new research space for developing polyamine metabolism-based therapy for HCC.

Keywords:  EVs; TME; mitochondria; polyamine; spermidine

DOI:  https://doi.org/10.3390/ijms25020996
Cancer Discov. 2024 Jan 25. OF1-OF22

EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.

Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Ramya S Kuna, Kacie A Traina, Camila Robles-Oteíza, Deborah Ayeni, Elizabeth M Kwong, Stellar Levy, Anna-Maria Globig, Matthew M Nobari, George Z Cheng, Sandra L Leibel, Robert J Homer, Reuben J Shaw, Christian M Metallo, Katerina Politi, Susan M Kaech.

The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.SIGNIFICANCE: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0434
Front Endocrinol (Lausanne). 2023 ;14 1331284

Immunometabolism, extracellular vesicles and cardiac injury.

Ana C M Omoto, Jussara M do Carmo, Alexandre A da Silva, John E Hall, Alan J Mouton.

  Recent evidence from our lab and others suggests that metabolic reprogramming of immune cells drives changes in immune cell phenotypes along the inflammatory-to-reparative spectrum and plays a critical role in mediating the inflammatory responses to cardiac injury (e.g. hypertension, myocardial infarction). However, the factors that drive metabolic reprogramming in immune cells are not fully understood. Extracellular vesicles (EVs) are recognized for their ability to transfer cargo such as microRNAs from remote sites to influence cardiac remodeling. Furthermore, conditions such as obesity and metabolic syndrome, which are implicated in the majority of cardiovascular disease (CVD) cases, can skew production of EVs toward pro-inflammatory phenotypes. In this mini-review, we discuss the mechanisms by which EVs may influence immune cell metabolism during cardiac injury and factors associated with obesity and the metabolic syndrome that can disrupt normal EV function. We also discuss potential sources of cardio-protective and anti-inflammatory EVs, such as brown adipose tissue. Finally, we discuss implications for future therapeutics.

Keywords:  immune system; macrophages; metabolism; microRNAs; myocardial infarction

DOI:  https://doi.org/10.3389/fendo.2023.1331284
Front Immunol. 2023 ;14 1334205

A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism.

Mehakpreet K Thind, Holm H Uhlig, Michael Glogauer, Nades Palaniyar, Celine Bourdon, Agnes Gwela, Christina L Lancioni, James A Berkley, Robert H J Bandsma, Amber Farooqui.

  Neutrophils are the most abundant innate immune cells. Multiple mechanisms allow them to engage a wide range of metabolic pathways for biosynthesis and bioenergetics for mediating biological processes such as development in the bone marrow and antimicrobial activity such as ROS production and NET formation, inflammation and tissue repair. We first discuss recent work on neutrophil development and functions and the metabolic processes to regulate granulopoiesis, neutrophil migration and trafficking as well as effector functions. We then discuss metabolic syndromes with impaired neutrophil functions that are influenced by genetic and environmental factors of nutrient availability and usage. Here, we particularly focus on the role of specific macronutrients, such as glucose, fatty acids, and protein, as well as micronutrients such as vitamin B3, in regulating neutrophil biology and how this regulation impacts host health. A special section of this review primarily discusses that the ways nutrient deficiencies could impact neutrophil biology and increase infection susceptibility. We emphasize biochemical approaches to explore neutrophil metabolism in relation to development and functions. Lastly, we discuss opportunities and challenges to neutrophil-centered therapeutic approaches in immune-driven diseases and highlight unanswered questions to guide future discoveries.

Keywords:  autophagy; glycolysis; immune mediated diseases; metabolic reprogramming; mitochondrial respiration; neutrophil differentiation

DOI:  https://doi.org/10.3389/fimmu.2023.1334205
Immunometabolism (Cobham). 2024 Jan;6(1): e00038

Inflammaging and fatty acid oxidation in monocytes and macrophages.

Victor Kruglov, In Hwa Jang, Christina D Camell.

  Fatty acid oxidation (FAO), primarily known as β-oxidation, plays a crucial role in breaking down fatty acids within mitochondria and peroxisomes to produce cellular energy and preventing metabolic dysfunction. Myeloid cells, including macrophages, microglia, and monocytes, rely on FAO to perform essential cellular functions and uphold tissue homeostasis. As individuals age, these cells show signs of inflammaging, a condition that includes a chronic onset of low-grade inflammation and a decline in metabolic function. These lead to changes in fatty acid metabolism and a decline in FAO pathways. Recent studies have shed light on metabolic shifts occurring in macrophages and monocytes during aging, correlating with an altered tissue environment and the onset of inflammaging. This review aims to provide insights into the connection of inflammatory pathways and altered FAO in macrophages and monocytes from older organisms. We describe a model in which there is an extended activation of receptor for advanced glycation end products, nuclear factor-κB (NF-κB) and the nod-like receptor family pyrin domain containing 3 inflammasome within macrophages and monocytes. This leads to an increased level of glycolysis, and also promotes pro-inflammatory cytokine production and signaling. As a result, FAO-related enzymes such as 5' AMP-activated protein kinase and peroxisome proliferator-activated receptor-α are reduced, adding to the escalation of inflammation, accumulation of lipids, and heightened cellular stress. We examine the existing body of literature focused on changes in FAO signaling within macrophages and monocytes and their contribution to the process of inflammaging.

Keywords:  aging; cytokines; fatty acid oxidation; inflammaging; inflammasome; inflammation; lipid droplets; macrophages; metabolic disease; microglia; monocytes

DOI:  https://doi.org/10.1097/IN9.0000000000000038
Atherosclerosis. 2024 Jan 14. pii: S0021-9150(24)00010-8. [Epub ahead of print]390 117450

Metabolic reprogramming of immune cells by mitochondrial division inhibitor-1 to prevent post-vascular injury neointimal hyperplasia.

Gustavo E Crespo-Avilan, Sauri Hernandez-Resendiz, Chrishan J Ramachandra, Victor Ungureanu, Ying-Hsi Lin, Shengjie Lu, Jürgen Bernhagen, Omar El Bounkari, Klaus T Preissner, Elisa A Liehn, Derek J Hausenloy.

  BACKGROUND AND AIMS: New treatments are needed to prevent neointimal hyperplasia that contributes to post-angioplasty and stent restenosis in patients with coronary artery disease (CAD) and peripheral arterial disease (PAD). We investigated whether modulating mitochondrial function using mitochondrial division inhibitor-1 (Mdivi-1) could reduce post-vascular injury neointimal hyperplasia by metabolic reprogramming of macrophages from a pro-inflammatory to anti-inflammatory phenotype.METHODS AND RESULTS: In vivo Mdivi-1 treatment of Apoe-/- mice fed a high-fat diet and subjected to carotid-wire injury decreased neointimal hyperplasia by 68%, reduced numbers of plaque vascular smooth muscle cells and pro-inflammatory M1-like macrophages, and decreased plaque inflammation, endothelial activation, and apoptosis, when compared to control. Mdivi-1 treatment of human THP-1 macrophages shifted polarization from a pro-inflammatory M1-like to an anti-inflammatory M2-like phenotype, reduced monocyte chemotaxis and migration to CCL2 and macrophage colony stimulating factor (M-CSF) and decreased secretion of pro-inflammatory mediators. Finally, treatment of pro-inflammatory M1-type-macrophages with Mdivi-1 metabolically reprogrammed them to an anti-inflammatory M2-like phenotype by inhibiting oxidative phosphorylation and attenuating the increase in succinate levels and correcting the decreased levels of arginine and citrulline.
CONCLUSIONS: We report that treatment with Mdivi-1 inhibits post-vascular injury neointimal hyperplasia by metabolic reprogramming macrophages towards an anti-inflammatory phenotype thereby highlighting the therapeutic potential of Mdivi-1 for preventing neointimal hyperplasia and restenosis following angioplasty and stenting in CAD and PAD patients.

Keywords:  Inflammation; Mdivi-1; Mitochondrial fission; Monocytes/macrophages; Neointimal hyperplasia; Vascular restenosis

DOI:  https://doi.org/10.1016/j.atherosclerosis.2024.117450
Front Oncol. 2023 ;13 1248339

Melatonin: a modulator in metabolic rewiring in T-cell malignancies.

Seema Rai, Gunja Roy, Younis Ahmad Hajam.

  Melatonin, (N-acetyl-5-methoxytryptamine) an indoleamine exerts multifaced effects and regulates numerous cellular pathways and molecular targets associated with circadian rhythm, immune modulation, and seasonal reproduction including metabolic rewiring during T cell malignancy. T-cell malignancies encompass a group of hematological cancers characterized by the uncontrolled growth and proliferation of malignant T-cells. These cancer cells exhibit a distinct metabolic adaptation, a hallmark of cancer in general, as they rewire their metabolic pathways to meet the heightened energy requirements and biosynthesis necessary for malignancies is the Warburg effect, characterized by a shift towards glycolysis, even when oxygen is available. In addition, T-cell malignancies cause metabolic shift by inhibiting the enzyme pyruvate Dehydrogenase Kinase (PDK) which in turn results in increased acetyl CoA enzyme production and cellular glycolytic activity. Further, melatonin plays a modulatory role in the expression of essential transporters (Glut1, Glut2) responsible for nutrient uptake and metabolic rewiring, such as glucose and amino acid transporters in T-cells. This modulation significantly impacts the metabolic profile of T-cells, consequently affecting their differentiation. Furthermore, melatonin has been found to regulate the expression of critical signaling molecules involved in T-cell activations, such as CD38, and CD69. These molecules are integral to T-cell adhesion, signaling, and activation. This review aims to provide insights into the mechanism of melatonin's anticancer properties concerning metabolic rewiring during T-cell malignancy. The present review encompasses the involvement of oncogenic factors, the tumor microenvironment and metabolic alteration, hallmarks, metabolic reprogramming, and the anti-oncogenic/oncostatic impact of melatonin on various cancer cells.

Keywords:  T-cell exhaustion; T-cell malignancy; cancer; melatonin; metabolic rewiring; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1248339
Brain Res. 2024 Jan 18. pii: S0006-8993(24)00026-X. [Epub ahead of print] 148772

Altered metabolism and DAM-signatures in female brains and microglia with aging.

Nicholas R W Cleland, Garrett J Potter, Courtney Buck, Daphne Quang, Dean Oldham, Mikaela Neal, Anthony Saviola, Christy S Niemeyer, Evgenia Dobrinskikh, Kimberley D Bruce.

  Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age-and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became 'male-like.' Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., ApoE, Trem2, LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17β-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD + with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

Keywords:  Aging; Alzheimer’s disease; Lipids; Lipoprotein lipase; Metabolism; Microglia; Sex-differences

DOI:  https://doi.org/10.1016/j.brainres.2024.148772
Front Pharmacol. 2023 ;14 1303913

New sights of immunometabolism and agent progress in colitis associated colorectal cancer.

Jingyue Zhang, Chaoyue Chen, Wei Yan, Yu Fu.

  Colitis associated colorectal cancer is a disease with a high incidence and complex course that develops from chronic inflammation and deteriorates after various immune responses and inflammation-induced attacks. Colitis associated colorectal cancer has the characteristics of both immune diseases and cancer, and the similarity of treatment models contributes to the similar treatment dilemma. Immunometabolism contributes to the basis of life and is the core of many immune diseases. Manipulating metabolic signal transduction can be an effective way to control the immune process, which is expected to become a new target for colitis associated colorectal cancer therapy. Immune cells participate in the whole process of colitis associated colorectal cancer development by transforming their functional condition via changing their metabolic ways, such as glucose, lipid, and amino acid metabolism. The same immune and metabolic processes may play different roles in inflammation, dysplasia, and carcinoma, so anti-inflammation agents, immunomodulators, and agents targeting special metabolism should be used in combination to prevent and inhibit the development of colitis associated colorectal cancer.

Keywords:  colitis associated colorectal cancer; immune adaption; immunometabolism; inflammation; metabolic reprogramming; metabolites; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2023.1303913
Mol Oncol. 2024 Jan 26.

Deciphering metabolic crosstalk in context: lessons from inflammatory diseases.

Fenne W M Verheijen, Thi N M Tran, Jung-Chin Chang, Femke Broere, Esther A Zaal, Celia R Berkers.

  Metabolism plays a crucial role in regulating the function of immune cells in both health and disease, with altered metabolism contributing to the pathogenesis of cancer and many inflammatory diseases. The local microenvironment has a profound impact on the metabolism of immune cells. Therefore, immunological and metabolic heterogeneity as well as the spatial organization of cells in tissues should be taken into account when studying immunometabolism. Here, we highlight challenges of investigating metabolic communication. Additionally, we review the capabilities and limitations of current technologies for studying metabolism in inflamed microenvironments, including single-cell omics techniques, flow cytometry-based methods (Met-Flow, single-cell energetic metabolism by profiling translation inhibition (SCENITH)), cytometry by time of flight (CyTOF), cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), and mass spectrometry imaging. Considering the importance of metabolism in regulating immune cells in diseased states, we also discuss the applications of metabolomics in clinical research, as well as some hurdles to overcome to implement these techniques in standard clinical practice. Finally, we provide a flowchart to assist scientists in designing effective strategies to unravel immunometabolism in disease-relevant contexts.

Keywords:  advanced metabolomics methods; immunometabolism; inflammatory diseases; metabolic crosstalk; metabolic heterogeneity; microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13588
Mol Neurobiol. 2024 Jan 24.

Integrated Bulk and Single-Cell RNA-Sequencing Reveals the Effects of Circadian Rhythm Disruption on the Metabolic Reprogramming of CD4+ T Cells in Alzheimer's Disease.

Weipin Weng, Jianhan Fu, Fan Cheng, Yixuan Wang, Jie Zhang.

  Although growing evidence suggests close correlations between Alzheimer's disease (AD) and circadian rhythm disruption (CRD), few studies have focused on the influence of circadian rhythm on levels of immune cells in AD. We aimed to delineate the mechanism underlying the effects of circadian related genes on T cell immune function in AD. A total of 112 brain samples were used to construct the CRD-related model by performing weighted gene co-expression network analysis and machine learning algorithms (LASSO, SVM-RFE, and RF). The ssGSEA method was used to calculate the CRDscore in order to quantify CRD status. Using single-cell transcriptome data of CSF cells, we investigated the CD4+ T cell metabolism and cell-cell communication in high- and low-risk CRD groups. Connectivity map (CMap) was applied to explore small molecule drugs targeting CRD, and the expression of the signature gene GPR4 was further validated in AD. The CRDscore algorithm, which is based on 23 circadian-related genes, can effectively classify the CRD status in AD datasets. The single-cell analysis revealed that the CD4+ T cells with high CRDscore were characterized by hypometabolism. Cell communication analysis revealed that CD4+ T cells might be involved in promoting CD8+ T cell adhesion under CRD, which may facilitate T cell infiltration into the brain parenchyma. Overall, this study indicates the potential connotation of circadian rhythm in AD, providing insights into understanding T cell metabolic reprogramming under CRD.

Keywords:  Alzheimer’s disease; Circadian rhythm; Metabolic reprogramming; ScRNA-seq; T cell

DOI:  https://doi.org/10.1007/s12035-023-03907-6
Front Immunol. 2023 ;14 1344697

The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization.

Yina An, Shuyu Tan, Jingjing Yang, Ting Gao, Yanjun Dong.

  Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization.

Keywords:  Hippo; inflammatory diseases; macrophage polarization; metabolism; regulatory network

DOI:  https://doi.org/10.3389/fimmu.2023.1344697
Cell Biochem Funct. 2024 Jan;42(1): e3926

One carbon metabolism and its implication in health and immune functions.

Shreya Dang, Arushi Jain, Garima Dhanda, Neetu Bhattacharya, Amit Bhattacharya, Sabyasachi Senapati.

  One carbon (1C) metabolism is critical for cellular viability and physiological homeostasis. Starting from its crucial involvement in purine biosynthesis to posttranslational modification of proteins, 1C metabolism contributes significantly to the development and cellular differentiation through methionine and folate cycles that are pivotal for cellular function. Genetic polymorphisms of several genes of these pathways are implicated in disease pathogenesis and drug metabolism. Metabolic products of 1C metabolism have significant roles in epigenetic modifications through DNA and histone protein methylation. Homocysteine is a product that has clinical significance in the diagnosis and prognosis of several critical illnesses, including chronic immune diseases and cancers. Regulation of the function and differentiation of immune cells, including T-cells, B-cells, macrophages, and so forth, are directly influenced by 1C metabolism and thus have direct implications in several immune disease biology. Recent research on therapeutic approaches is targeting nuclear, cytoplasmic, and mitochondrial 1C metabolism to manage and treat metabolic (i.e., type 2 diabetes), neurodegenerative (i.e., Alzheimer's disease), or immune (i.e., rheumatoid arthritis) diseases. 1C metabolism is being explored for therapeutic intervention as a common determinant for a spectrum of immune and metabolic diseases. Identifying the association or correlation between essential metabolic products of this pathway and disease onset or prognosis would further facilitate the clinical monitoring of diseases.

Keywords:  chronic disease; folic acid metabolism; immune function; metabolic diseases; one carbon metabolism; purine biosynthesis

DOI:  https://doi.org/10.1002/cbf.3926
Front Immunol. 2023 ;14 1307228

Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.

Yanru Long, Houhui Shi, Yuedong He, Xiaorong Qi.

  Tumor metabolism and tumor immunity are inextricably linked. Targeting the metabolism of tumors is a point worth studying in tumor immunotherapy. Recently, the influence of the metabolism of tumors and immune cells on the occurrence, proliferation, metastasis, and prognosis of tumors has attracted more attention. Tumor tissue forms a specific tumor microenvironment (TME). In addition to tumor cells, there are also immune cells, stromal cells, and other cells in TME. To adapt to the environment, tumor cells go through the metabolism reprogramming of various substances. The metabolism reprogramming of tumor cells may further affect the formation of the tumor microenvironment and the function of a variety of cells, especially immune cells, eventually promoting tumor development. Therefore, it is necessary to study the metabolism of tumor cells and its effects on immune cells to guide tumor immunotherapy. Inhibiting tumor metabolism may restore immune balance and promote the immune response in tumors. This article will describe glucose metabolism, lipid metabolism, amino acid metabolism, and immune cells in tumors. Besides, the impact of metabolism on the immune cells in TME is also discussed for analyzing and exploring tumor immunotherapy.

Keywords:  amino acid metabolism; glucose metabolism; immunotherapy; lipid metabolism; metabolism reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1307228
Nat Aging. 2024 Jan 24.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

DOI: https://doi.org/10.1038/s43587-023-00560-5
Front Immunol. 2023 ;14 1327977

Reduced mitochondrial respiration in peripheral T cells after paediatric heamatopoietic stem cell transplantation.

Kasper Mølgaard, Katrine Kielsen, Marianne Ifversen, Özcan Met, Inge Marie Svane, Klaus Müller.

  Background: Recovery and functional differentiation of T-cell subsets are central for the development of immune function and complications after allogeneic hematopoietic stem cell transplantation (HSCT), but little is known about the cellular respiration and factors influencing T-cell metabolic fitness during immune maturation after HSCT.Method: We included 20 HSCT patients and analysed mitochondrial oxidative phosphorylation and mitochondrial fitness in peripheral blood mononuclear cell samples collected at days +90 and +180 after HSCT.
Results: Phenotypic analysis revealed lower overall T-cell counts, lower CD4+/CD8+ ratio and a skewed distribution of early T-cell subsets at day +90, gradually recovering by day +180. Although ATP turnover in HSCT patients was similar to healthy controls, the spare respiratory capacity (SRC) of T cells, reflecting the available energy reserve, was significantly reduced at day +90 and +180 compared to healthy controls. This reduction in SRC was not correlated with the occurrence of acute graft-versus-host disease (aGVHD), the intensity of conditioning regimens and markers of T-cell exhaustion.
Conclusion: We found significantly depressed SRC until six months post-HSCT, but we were not able to identify transplant-related risk factors or associations with the clinical outcome.

Keywords:  T cells; acute graft-versus-host disease; hematopoietic stem cell transplantation; mitochondrial fitness; real-time metabolism; spare respiratory capacity

DOI:  https://doi.org/10.3389/fimmu.2023.1327977
Vet Microbiol. 2024 Jan 19. pii: S0378-1135(24)00022-1. [Epub ahead of print]290 110000

Inhibition of pseudorabies virus replication via upregulated interferon response by targeting 7-dehydrocholesterol reductase.

Zicheng Ma, Lei Guo, Mengjiao Pan, Chenlong Jiang, Depeng Liu, Yanni Gao, Juan Bai, Ping Jiang, Xing Liu.

  Pseudorabies virus (PRV) is an alpha-herpesvirus capable of infecting a range of animal species, particularly its natural host, pigs, resulting in substantial economic losses for the swine industry. Recent research has shed light on the significant role of cholesterol metabolism in the replication of various viruses. However, the specific role of cholesterol metabolism in PRV infection remains unknown. Here, we demonstrated that the expression of 7-dehydrocholesterol reductase (DHCR7) is upregulated following PRV infection, as evidenced by the proteomic analysis. Subsequently, we showed that DHCR7 plays a crucial role in promoting PRV replication by converting 7-dehydrocholesterol (7-DHC) into cholesterol, leading to increased cellular cholesterol levels. Importantly, DHCR7 inhibits the phosphorylation of interferon regulatory factor 3 (IRF3), resulting in reduced levels of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs). Finally, we revealed that the DHCR7 inhibitor, trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride (AY9944), significantly suppresses PRV replication both in vitro and in vivo. Taken together, the study has established a connection between cholesterol metabolism and PRV replication, offering novel insights that may guide future approaches to the prevention and treatment of PRV infections.

Keywords:  Cholesterol; DHCR7; Interferon; PRV

DOI:  https://doi.org/10.1016/j.vetmic.2024.110000
Genes Immun. 2024 Jan 22.

Take my breath away-mitochondrial dysfunction drives CD8+ T cell exhaustion.

Felix Clemens Richter, Mariia Saliutina, Ahmed N Hegazy, Andreas Bergthaler.

DOI: https://doi.org/10.1038/s41435-023-00233-8
Res Sq. 2024 Jan 12. pii: rs.3.rs-3830704. [Epub ahead of print]

HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells.

Lewis Shi, Hongxing Shen, Logan Mullen, Oluwagbemiga Ojo, Chuan Xing, Abdelrahman Yassin, Zach Lewis, James Bonner.

The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1α in T cells (HIF1α -/- ) and glycolytic inhibition significantly abrogate IFN-γ induction. Conversely, HIF1α stabilization in T cells by hypoxia and VHL deletion (VHL -/- ) promotes IFN-γ production. Mechanistically, reduced IFN-γ production in hypoxic HIF1α -/- T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1α -/- T cells are less able to kill tumor cells, and HIF1α -/- tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1α in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-γ production in hypoxic HIF1α -/- T cells and re-sensitizes HIF1α -/- tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1α-anaerobic glycolysis as a principal mediator of IFN-γ induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need.

DOI: https://doi.org/10.21203/rs.3.rs-3830704/v1
Hepatology. 2024 Jan 24.

Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of hepatic stellate cells.

Yujia Xia, Yu Wang, Qi Xiong, Jiayi He, Han Wang, Mozaffarul Islam, Xinyu Zhou, Alex Kim, Hongji Zhang, Hai Huang, Allan Tsung.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH)-fibrosis is a reversible stage of liver disease accompanied by inflammatory cells infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote hepatocellular carcinoma in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis.APPROACH AND RESULTS: Following 12 weeks of Western diet (WD)/carbon tetrachloride (CCl4), MASH-fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked-out for peptidyl arginine deaminase type IV (PAD4-/-), significantly attenuated the development of MASH-fibrosis. NETs were demonstrated to induce hepatic stellate cells (HSCs) activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 (TLR3) induced cyclooxygenase-2 (COX-2) activation and prostaglandin E2 (PGE2) production with subsequent HSC activation and liver fibrosis. Inhibiting COX-2 with celecoxib reduced fibrosis in our MASH model.
CONCLUSIONS: Our findings implicate NETs playing a critical role in the development of MASH-hepatic fibrosis by inducing metabolic reprogramming of HSCs via the TLR3/COX-2/PGE2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.

DOI: https://doi.org/10.1097/HEP.0000000000000762
iScience. 2024 Jan 19. 27(1): 108775

Influenza A virus selectively elevates prostaglandin E2 formation in pro-resolving macrophages.

Paul M Jordan, Kerstin Günther, Vivien Nischang, Yuping Ning, Stefanie Deinhardt-Emmer, Christina Ehrhardt, Oliver Werz.

  Respiratory influenza A virus (IAV) infections are major health concerns worldwide, where bacterial superinfections substantially increase morbidity and mortality. The underlying mechanisms of how IAV impairs host defense remain elusive. Macrophages are pivotal for the innate immune response and crucially regulate the entire inflammatory process, occurring as inflammatory M1- or pro-resolving M2-like phenotypes. Lipid mediators (LM), produced from polyunsaturated fatty acids by macrophages, are potent immune regulators and impact all stages of inflammation. Using LM metabololipidomics, we show that human pro-resolving M2-macrophages respond to IAV infections with specific and robust production of prostaglandin (PG)E2 along with upregulation of cyclooxygenase-2 (COX-2), which persists after co-infection with Staphylococcus aureus. In contrast, cytokine/interferon production in macrophages was essentially unaffected by IAV infection, and the functionality of M1-macrophages was not influenced. Conclusively, IAV infection of M2-macrophages selectively elevates PGE2 formation, suggesting inhibition of the COX-2/PGE2 axis as strategy to limit IAV exacerbation.

Keywords:  Immunology; Virology

DOI:  https://doi.org/10.1016/j.isci.2023.108775
J Invest Dermatol. 2024 Jan 19. pii: S0022-202X(24)00023-X. [Epub ahead of print]

LPCAT1 facilitates keratinocyte hyperproliferation and skin inflammation in psoriasis via regulating GLUT3.

Yingjian Huang, Yuqian Wang, Yunyue Zhen, Wancheng Liu, Yan Wang, Ruijie Wang, Ning Wang, Shan Huang, Jianjun Yan, Qing Sun.

  Psoriasis is a chronic and relapsing inflammatory skin disorder characterized by keratinocyte hyperproliferation and immune cell infiltration. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been identified as a cancer promoter in cutaneous squamous cell carcinoma by us, yet its role in psoriasis remains elusive. In this study, we report that LPCAT1 is highly expressed in psoriatic skin lesions. LPCAT1 promotes keratinocyte hyperproliferation and enhances the secretion of IL-1β, IL-6, CXCL10, CCL20, S100A9, and platelet-activating factor (PAF). In psoriasiform keratinocytes, LPCAT1 promotes proliferation and inflammatory mediator production by activating protein kinase B/NF-κB and STAT3 signaling pathways. Furthermore, LPCAT1 inhibition attenuated epidermal hyperplasia and relieved skin inflammation in imiquimod (IMQ)-treated mice. Importantly, we identify the glucose transporter GLUT3, a recently reported promising target to mitigate Th17-cell-mediated inflammatory diseases, as a critical downstream effector of LPCAT1. GLUT3 deficiency impaired the proliferation and inflammation of psoriatic keratinocytes. LPCAT1 regulates GLUT3 in keratinocytes via NF-κB/STAT3 signaling, enhancing keratinocyte glycolysis and promoting pro-proliferative and proinflammatory effects. In addition, suppressing GLUT3 in mice alleviated IMQ-induced dermatitis. Taken together, our study indicates the critical role of the LPCAT1-GLUT3 axis in psoriasis pathogenesis and proposes LPCAT1 or GLUT3 as a potential therapeutic target for psoriasis.

Keywords:  GLUT3; LPCAT1; keratinocyte; psoriasis

DOI:  https://doi.org/10.1016/j.jid.2024.01.004
Cell Rep. 2024 Jan 19. pii: S2211-1247(24)00016-0. [Epub ahead of print]43(2): 113688

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Xiu-Ming Li, Yun Yang, Fu-Quan Jiang, Guang Hu, Shan Wan, Wen-Ying Yan, Xiao-Shun He, Fei Xiao, Xue-Mei Yang, Xin Guo, Jun-Hou Lu, Xiao-Qin Yang, Jun-Jie Chen, Wen-Long Ye, Yue Liu, Kuang He, Han-Xiao Duan, Yu-Jia Zhou, Wen-Juan Gan, Feng Liu, Hua Wu.

  Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Keywords:  CP: Cancer; CP: Immunology

DOI:  https://doi.org/10.1016/j.celrep.2024.113688
EMBO Rep. 2024 Jan 23.

Mitochondrial translocation of TFEB regulates complex I and inflammation.

Chiara Calabrese, Hendrik Nolte, Melissa R Pitman, Raja Ganesan, Philipp Lampe, Raymond Laboy, Roberto Ripa, Julia Fischer, Ruhi Polara, Sameer Kumar Panda, Sandhya Chipurupalli, Saray Gutierrez, Daniel Thomas, Stuart M Pitson, Adam Antebi, Nirmal Robinson.

  TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

Keywords:  LONP1; Metabolism; Mitochondria; Salmonella; TFEB

DOI:  https://doi.org/10.1038/s44319-024-00058-0
Parasite Immunol. 2024 Jan;46(1): e13020

Activation of murine macrophages by membrane proteins from Tritrichomonas foetus grown on iron- and calcium-rich conditions.

Antonio Euan-Canto, Julio César Torres-Romero, María Elizbeth Alvarez-Sánchez, Victor Ermilo Arana-Argáez, Karla Acosta-Viana, Emanuel Ceballos-Góngora, Laura Vázquez-Carrillo, Leidi Alvarez-Sánchez.

  Tritrichomonas foetus is a protozoan parasite that causes a venereal disease in cattle limiting reproduction by abortions and sterility. The immune response against this parasite is poorly understood. Since the iron and calcium ions are important regulators of the microenvironment of the urogenital tract in cattle, we decided to evaluate the role of these divalent cations on the antigenicity of membrane proteins of T. foetus on macrophage activation as one of the first inflammatory responses towards this pathogen. Colorimetric methods and ELISA were used to detect the nitric oxide and oxygen peroxide production and expression of cytokines in culture supernatant from macrophage incubated with membrane proteins from T. foetus cultured in iron- and calcium-rich conditions. qRT-PCR assays were used to evaluate the transcript expression of genes involved in the inflammatory response on the macrophages. The membrane proteins used for in vitro stimulation caused the up-regulation of the iNOS and NOX-2 genes as well as the generation of NO and H2 O2 in murine macrophages on a dependent way of the metal concentrations. Additionally, after stimulation, macrophages showed a considerable rise in pro-inflammatory cytokines and a downregulation of anti-inflammatory cytokines, as well as up-regulation in the transcription of the TLR4 and MyD88 genes. These data suggest that membrane proteins of T. foetus induced by iron and calcium can activate an inflammatory specific macrophage response via TLR4/MyD88 signalling pathway.

Keywords:  Tritrichomonas foetus; calcium; immunomodulatory; iron; macrophages

DOI:  https://doi.org/10.1111/pim.13020