bims-imicid 2023-03-19 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒03‒19
33 papers selected by
Dylan Ryan
University of Cambridge

Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.
The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response.
Cord serum metabolic signatures of future progression to immune-mediated diseases.
Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications.
Targeting immunometabolism against acute lung injury.
4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.
TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.
Resveratrol attenuates staphylococcal enterotoxin B-activated immune cell metabolism via upregulation of miR-100 and suppression of mTOR signaling pathway.
Metabolic Challenges in Anticancer CD8 T Cell Functions.
An optimized reporter of the transcription factor hypoxia-inducible factor 1α reveals complex HIF-1α activation dynamics in single cells.
LDHA as a regulator of T cell fate and its mechanisms in disease.
Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment.
Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2.
Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.
Gut Microbial Metabolites on Host Immune Responses in Health and Disease.
Inhibition of glutaminase 1 activity reverses airway hyperresponsiveness and decreases IL-1β+ M1s and IL-17 producing ILC3s in high-fat diet-fed obese mice.
Immunometabolomics provides a new perspective for studying systemic lupus erythematosus.
UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis.
High-content assay to measure mitochondrial function and bacterial vacuole size in infected human primary macrophages.
Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells.
Metabolic regulation of the circadian clock in classically and alternatively activated macrophages.
The effect of sodium thiosulfate on immune cell metabolism during porcine hemorrhage and resuscitation.
Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis.
HIV-differentiated metabolite N-Acetyl-L-Alanine dysregulates human natural killer cell responses to Mycobacterium tuberculosis infection.
The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids.
Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.
Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
SnapShot: Mitochondrial signaling.
Novel arginase inhibitor, AZD0011, demonstrates immune cell stimulation and anti-tumor efficacy with diverse combination partners.
The F1Fo-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism.
HK2: Gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions.
Cholesterol confers ferroptosis resistance onto myeloid-biased hematopoietic stem cells and prevents irradiation-induced myelosuppression.
Tissue-specific macrophages: how they develop and choreograph tissue biology.

Immunity. 2023 Mar 07. pii: S1074-7613(23)00092-4. [Epub ahead of print]

Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.

Jinzhi Duan, Juan D Matute, Lukas W Unger, Thomas Hanley, Alexandra Schnell, Xi Lin, Niklas Krupka, Paul Griebel, Conner Lambden, Brandon Sit, Joep Grootjans, Michal Pyzik, Felix Sommer, Sina Kaiser, Maren Falk-Paulsen, Helmut Grasberger, John Y Kao, Tobias Fuhrer, Hai Li, Donggi Paik, Yunjin Lee, Samuel Refetoff, Jonathan N Glickman, Adrienne W Paton, Lynn Bry, James C Paton, Uwe Sauer, Andrew J Macpherson, Philip Rosenstiel, Vijay K Kuchroo, Matthew K Waldor, Jun R Huh, Arthur Kaser, Richard S Blumberg.

  Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

Keywords:  Citrobacter rodentium; ROS signals; TH17 cells; commensal bacterial; epithelial endoplasmic reticulum stress; inflammatory bowel disease; purine metabolism

DOI:  https://doi.org/10.1016/j.immuni.2023.02.018
J Clin Invest. 2023 Mar 15. pii: e160463. [Epub ahead of print]133(6):

The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response.

Yi-Rong Zeng, Jun-Bin Song, Dezheng Wang, Zi-Xuan Huang, Cheng Zhang, Yi-Ping Sun, Gang Shu, Yue Xiong, Kun-Liang Guan, Dan Ye, Pu Wang.

  Pathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is also secreted from the cell, but whether secreted ITA functions as a signaling molecule is unclear. Here, we identified ITA as an orthosteric agonist of the GPCR OXGR1, with an EC50 of approximately 0.3 mM, which was in the same range as the physiological concentration of extracellular ITA upon macrophage activation. ITA activated OXGR1 to induce Ca2+ mobilization, ERK phosphorylation, and endocytosis of the receptor. In a mouse model of pulmonary infection with bacterial Pseudomonas aeruginosa, ITA stimulated Oxgr1-dependent mucus secretion and transport in respiratory epithelium, the primary innate defense mechanism of the airway. Our study thus identifies ITA as a bona fide ligand for OXGR1 and the ITA/OXGR1 paracrine signaling pathway during the pulmonary innate immune response.

Keywords:  G protein–coupled receptors; Metabolism

DOI:  https://doi.org/10.1172/JCI160463
iScience. 2023 Mar 17. 26(3): 106268

Cord serum metabolic signatures of future progression to immune-mediated diseases.

Tuulia Hyötyläinen, Bagavathy Shanmugam Karthikeyan, Tannaz Ghaffarzadegan, Eric W Triplett, Matej Orešič, Johnny Ludvigsson.

  Previous prospective studies suggest that progression to autoimmune diseases is preceded by metabolic dysregulation, but it is not clear which metabolic changes are disease-specific and which are common across multiple immune-mediated diseases. Here we investigated metabolic profiles in cord serum in a general population cohort (All Babies In Southeast Sweden; ABIS), comprising infants who progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n = 12), celiac disease (n = 28), juvenile idiopathic arthritis (n = 9), inflammatory bowel disease (n = 7), and hypothyroidism (n = 6); and matched controls (n = 270). We observed elevated levels of multiple triacylglycerols (TGs) an alteration in several gut microbiota related metabolites in the autoimmune groups. The most distinct differences were observed in those infants who later developed HT. The specific similarities observed in metabolic profiles across autoimmune diseases suggest that they share specific common metabolic phenotypes at birth that contrast with those of healthy controls.

Keywords:  Health sciences; Human metabolism; Immunology; Lipidomics; Metabolomics

DOI:  https://doi.org/10.1016/j.isci.2023.106268
Lupus. 2023 Mar 13. 9612033231164635

Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications.

Anjali S Yennemadi, Joseph Keane, Gina Leisching.

  The association of dysregulated metabolism in systemic lupus erythematosus (SLE) pathogenesis has prompted investigations into metabolic rewiring and the involvement of mitochondrial metabolism as a driver of disease through NLRP3 inflammasome activation, disruption of mitochondrial DNA maintenance, and pro-inflammatory cytokine release. The use of Agilent Seahorse Technology to gain functional in situ metabolic insights of selected cell types from SLE patients has identified key parameters that are dysregulated during disease. Mitochondrial functional assessments specifically can detect dysfunction through oxygen consumption rate (OCR), spare respiratory capacity, and maximal respiration measurements, which, when coupled with disease activity scores could show potential as markers of disease activity. CD4+ and CD8 + T cells have been assessed in this way and show that oxygen consumption rate, spare respiratory capacity, and maximal respiration are blunted in CD8 + T cells, with results not being as clear cut in CD4 + T cells. Additionally, glutamine, processed by mitochondrial substrate level phosphorylation is emerging as a key role player in the expansion and differentiation of Th1, Th17, ϒδ T cells, and plasmablasts. The role that circulating leukocytes play in acting as bioenergetic biomarkers of diseases such as diabetes suggests that this may also be a tool to detect preclinical SLE. Therefore, the metabolic characterization of immune cell subsets and the collection of metabolic data during interventions is also essential. The delineation of the metabolic tuning of immune cells in this way could lead to novel strategies in treating metabolically demanding processes characteristic of autoimmune diseases such as SLE.

Keywords:  Systemic lupus erythematosus; autoimmunity; glutamate; glutamine; glycolysis; immunometabolism; inflammation; mitochondria; oxygen consumption rate (OCR); substrate level phosphorylation

DOI:  https://doi.org/10.1177/09612033231164635
Clin Immunol. 2023 Mar 12. pii: S1521-6616(23)00068-2. [Epub ahead of print]249 109289

Targeting immunometabolism against acute lung injury.

Li Ning, Zou Shishi, Wang Bo, Lin Huiqing.

  Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions triggered by multiple intra- and extra-pulmonary injury factors, characterized by complicated molecular mechanisms and high mortality. Great strides have been made in the field of immunometabolism to clarify the interplay between intracellular metabolism and immune function in the past few years. Emerging evidence unveils the crucial roles of immunometabolism in inflammatory response and ALI. During ALI, both macrophages and lymphocytes undergo robust metabolic reprogramming and discrete epigenetic changes after activated. Apart from providing ATP and biosynthetic precursors, these metabolic cellular reactions and processes in lung also regulate inflammation and immunity.In fact, metabolic reprogramming involving glucose metabolism and fatty acidoxidation (FAO) acts as a double-edged sword in inflammatory response, which not only drives inflammasome activation but also elicits anti-inflammatory response. Additionally, the features and roles of metabolic reprogramming in different immune cells are not exactly the same. Here, we outline the evidence implicating how adverse factors shape immunometabolism in differentiation types of immune cells during ALI and summarize key proteins associated with energy expenditure and metabolic reprogramming. Finally, novel therapeutic targets in metabolic intermediates and enzymes together with current challenges in immunometabolism against ALI were discussed.

Keywords:  ALI; Drugtarget; Immunometabolism; Inflammation; Macrophages

DOI:  https://doi.org/10.1016/j.clim.2023.109289
Mol Med. 2023 Mar 14. 29(1): 31

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.

Sunyue He, Yuchen Zhao, Guoxing Wang, Qiaofang Ke, Nan Wu, Lusi Lu, Jiahua Wu, Shuiya Sun, Weihua Jin, Wenjing Zhang, Jiaqiang Zhou.

  BACKGROUND: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming.METHODS: The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment.
RESULTS: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1β production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment.
CONCLUSIONS: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Keywords:  4-Octyl itaconate; Islet injury; Macrophage activation; Type 1 diabetes

DOI:  https://doi.org/10.1186/s10020-023-00626-5
Free Radic Biol Med. 2023 Mar 11. pii: S0891-5849(23)00105-3. [Epub ahead of print]200 102-116

TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.

Jia-Feng Sha, Qiu-Meng Xie, Ning Chen, Si-Ming Song, Ya Ruan, Cui-Cui Zhao, Qian Liu, Rong-Hua Shi, Xu-Qin Jiang, Guang-He Fei, Hui-Mei Wu.

  As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2-/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2-/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2-/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2-/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2-/- mice abolished while transfer of TLR2-/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.

Keywords:  Allergic airway inflammation (AAI); Glycolysis; Oxidative stress; Resident alveolar macrophage (r-AM); Toll like receptor 2 (TLR2); hif1α

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.007
Front Pharmacol. 2023 ;14 1106733

Resveratrol attenuates staphylococcal enterotoxin B-activated immune cell metabolism via upregulation of miR-100 and suppression of mTOR signaling pathway.

Hasan Alghetaa, Amira Mohammed, Narendra Singh, Kiesha Wilson, Goushuai Cai, Nagireddy Putluri, Mitzi Nagarkatti, Prakash Nagarkatti.

  Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of insults, such as bacterial and viral infections, including SARS-CoV-2, leading to high mortality. In the murine model of ARDS induced by Staphylococcal enterotoxin-B (SEB), our previous studies showed that while SEB triggered 100% mortality, treatment with Resveratrol (RES) completely prevented such mortality by attenuating inflammation in the lungs. In the current study, we investigated the metabolic profile of SEB-activated immune cells in the lungs following treatment with RES. RES-treated mice had higher expression of miR-100 in the lung mononuclear cells (MNCs), which targeted mTOR, leading to its decreased expression. Also, Single-cell RNA-seq (scRNA seq) unveiled the decreased expression of mTOR in a variety of immune cells in the lungs. There was also an increase in glycolytic and mitochondrial respiration in the cells from SEB + VEH group in comparison with SEB + RES group. Together these data suggested that RES alters the metabolic reprogramming of SEB-activated immune cells, through suppression of mTOR activation and its down- and upstream effects on energy metabolism. Also, miR-100 could serve as novel potential therapeutic molecule in the amelioration of ARDS.

Keywords:  ARDS (acute respiratory disease syndrome); MiR-100; ScRNA; T-cell metabolism; mTOR; metabolome; resveratrol; staphylococcal enterotoxin B (SEB)

DOI:  https://doi.org/10.3389/fphar.2023.1106733
Immune Netw. 2023 Feb;23(1): e9

Metabolic Challenges in Anticancer CD8 T Cell Functions.

Andrea M Amitrano, Minsoo Kim.

  Cancer immunotherapies continue to face numerous obstacles in the successful treatment of solid malignancies. While immunotherapy has emerged as an extremely effective treatment option for hematologic malignancies, it is largely ineffective against solid tumors due in part to metabolic challenges present in the tumor microenvironment (TME). Tumor-infiltrating CD8+ T cells face fierce competition with cancer cells for limited nutrients. The strong metabolic suppression in the TME often leads to impaired T-cell recruitment to the tumor site and hyporesponsive effector functions via T-cell exhaustion. Growing evidence suggests that mitochondria play a key role in CD8+ T-cell activation, migration, effector functions, and persistence in tumors. Therefore, targeting the mitochondrial metabolism of adoptively transferred T cells has the potential to greatly improve the effectiveness of cancer immunotherapies in treating solid malignancies.

Keywords:  CD8 Positive T lymphocytes; Chimeric antigen receptor therapy; Metabolism; Mitochondria

DOI:  https://doi.org/10.4110/in.2023.23.e9
J Biol Chem. 2023 Mar 10. pii: S0021-9258(23)00241-7. [Epub ahead of print] 104599

An optimized reporter of the transcription factor hypoxia-inducible factor 1α reveals complex HIF-1α activation dynamics in single cells.

Stevan Jeknić, Takamasa Kudo, Joanna J Song, Markus W Covert.

  Immune cells adopt a variety of metabolic states to support their many biological functions, which include fighting pathogens, removing tissue debris, and tissue remodeling. One of the key mediators of these metabolic changes is the transcription factor hypoxia-inducible factor 1α (HIF-1α). Single-cell dynamics have been shown to be an important determinant of cell behavior; however, despite the importance of HIF-1α, little is known about its single-cell dynamics or their effect on metabolism. To address this knowledge gap, here we optimized a HIF-1α fluorescent reporter and applied it to study single-cell dynamics. First, we showed that single cells are likely able to differentiate multiple levels of prolyl hydroxylase inhibition, a marker of metabolic change, via HIF-1α activity. We then applied a physiological stimulus known to trigger metabolic change, interferon-γ, and observed heterogeneous, oscillatory HIF-1α responses in single cells. Finally, we input these dynamics into a mathematical model of HIF-1α-regulated metabolism, and discovered a profound difference between cells exhibiting high versus low HIF-1α activation. Specifically, we found cells with high HIF-1α activation are able to meaningfully reduce flux through the tricarboxylic acid cycle and show a notable increase in the NAD+/NADH ratio compared to cells displaying low HIF-1α activation. Altogether, this work demonstrates an optimized reporter for studying HIF-1α in single cells and reveals previously unknown principles of HIF-1α activation.

Keywords:  fluorescence; hypoxia-inducible factor (HIF); mathematical modeling; microscopy; systems biology

DOI:  https://doi.org/10.1016/j.jbc.2023.104599
Biomed Pharmacother. 2023 Feb;pii: S0753-3322(22)01553-0. [Epub ahead of print]158 114164

LDHA as a regulator of T cell fate and its mechanisms in disease.

Maosha Dai, Li Wang, Juexi Yang, Jiayi Chen, Xiaoke Dou, Rui Chen, Yangyang Ge, Yun Lin.

  T cells are the main force of anti-infection and antitumor and are also involved in autoimmune diseases. During the development of these diseases, T cells need to rapidly produce large amounts of energy to satisfy their activation, proliferation, and differentiation. In this review, we introduced lactate dehydrogenase A(LDHA), predominantly involved in glycolysis, which provides energy for T cells and plays a dual role in disease by mediating lactate production, non-classical enzyme activity, and oxidative stress. Mechanistically, the signaling molecule can interact with the LDHA promoter or regulate LDHA activity through post-translational modifications. These latest findings suggest that modulation of LDHA may have considerable therapeutic effects in diseases where T-cell activation is an important pathogenesis.

Keywords:  Immune-related diseases; Immunometabolism; Lactate dehydrogenase A (LDHA); T lymphocytes

DOI:  https://doi.org/10.1016/j.biopha.2022.114164
Mol Cells. 2023 Mar 17.

Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment.

Jialin Feng, Oliver J Read, Albena T Dinkova-Kostova.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of pro-inflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.

Keywords:  Keap1; Nrf2; anti-tumor immunity; immunosuppression; tumor microenvironment

DOI:  https://doi.org/10.14348/molcells.2023.2183
Eur J Pharmacol. 2023 Mar 13. pii: S0014-2999(23)00166-8. [Epub ahead of print] 175655

Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2.

Marek Samec, Alena Mazurakova, Vincent Lucansky, Lenka Koklesova, Renata Pecova, Martin Pec, Olga Golubnitschaja, Raghad Khalid Al-Ishaq, Martin Caprnda, Ludovit Gaspar, Robert Prosecky, Katarina Gazdikova, Mariusz Adamek, Dietrich Büsselberg, Peter Kruzliak, Peter Kubatka.

  Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.

Keywords:  Cancer cells; Carcinogenesis; Flavonoids; Metabolic reprogramming; Metabolism

DOI:  https://doi.org/10.1016/j.ejphar.2023.175655
J Immunother Cancer. 2023 03;pii: e006522. [Epub ahead of print]11(3):

Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.

Konstantinos Lontos, Yiyang Wang, Supriya K Joshi, Andrew T Frisch, McLane J Watson, Alok Kumar, Ashley V Menk, Yupeng Wang, Rachel Cumberland, Jason Lohmueller, Esteban Carrizosa, Benjamin Boyerinas, Greg M Delgoffe.

  BACKGROUND: Cellular immunotherapies for cancer represent a means by which a patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral T cells to tumor targets, showing remarkable potency in blood cancers. However, due to several resistance mechanisms, CAR-T cell therapies remain ineffective in solid tumors. We and others have shown the tumor microenvironment harbors a distinct metabolic landscape that produces a barrier to immune cell function. Further, altered differentiation of T cells within tumors induces defects in mitochondrial biogenesis, resulting in severe cell-intrinsic metabolic deficiencies. While we and others have shown murine T cell receptor (TCR)-transgenic cells can be improved through enhanced mitochondrial biogenesis, we sought to determine whether human CAR-T cells could be enabled through a metabolic reprogramming approach.MATERIALS AND METHODS: Anti-EGFR CAR-T cells were infused in NSG mice which bore A549 tumors. The tumor infiltrating lymphocytes were analyzed for exhaustion and metabolic deficiencies. Lentiviruses carrying PPAR-gamma coactivator 1α (PGC-1α), PGC-1αS571A and NT-PGC-1α constructs were used to co-transduce T cells with anti-EGFR CAR lentiviruses. We performed metabolic analysis via flow cytometry and Seahorse analysis in vitro as well as RNA sequencing. Finally, we treated therapeutically A549-carrying NSG mice with either PGC-1α or NT-PGC-1α anti-EGFR CAR-T cells. We also analyzed the differences in the tumor-infiltrating CAR-T cells when PGC-1α is co-expressed.
RESULTS: Here, in this study, we show that an inhibition resistant, engineered version of PGC-1α, can metabolically reprogram human CAR-T cells. Transcriptomic profiling of PGC-1α-transduced CAR-T cells showed this approach effectively induced mitochondrial biogenesis, but also upregulated programs associated with effector functions. Treatment of immunodeficient animals bearing human solid tumors with these cells resulted in substantially improved in vivo efficacy. In contrast, a truncated version of PGC-1α, NT-PGC-1α, did not improve the in vivo outcomes.
CONCLUSIONS: Our data further support a role for metabolic reprogramming in immunomodulatory treatments and highlight the utility of genes like PGC-1α as attractive candidates to include in cargo along with chimeric receptors or TCRs for cell therapy of solid tumors.

Keywords:  Cell Engineering; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Translational Medical Research

DOI:  https://doi.org/10.1136/jitc-2022-006522
Immune Netw. 2023 Feb;23(1): e6

Gut Microbial Metabolites on Host Immune Responses in Health and Disease.

Jong-Hwi Yoon, Jun-Soo Do, Priyanka Velankanni, Choong-Gu Lee, Ho-Keun Kwon.

  Intestinal microorganisms interact with various immune cells and are involved in gut homeostasis and immune regulation. Although many studies have discussed the roles of the microorganisms themselves, interest in the effector function of their metabolites is increasing. The metabolic processes of these molecules provide important clues to the existence and function of gut microbes. The interrelationship between metabolites and T lymphocytes in particular plays a significant role in adaptive immune functions. Our current review focuses on 3 groups of metabolites: short-chain fatty acids, bile acids metabolites, and polyamines. We collated the findings of several studies on the transformation and production of these metabolites by gut microbes and explained their immunological roles. Specifically, we summarized the reports on changes in mucosal immune homeostasis represented by the Tregs and Th17 cells balance. The relationship between specific metabolites and diseases was also analyzed through latest studies. Thus, this review highlights microbial metabolites as the hidden treasure having potential diagnostic markers and therapeutic targets through a comprehensive understanding of the gut-immune interaction.

Keywords:  Bile acids; Immunomodulation; Microbiota; Polyamines; Short-chain fatty acid

DOI:  https://doi.org/10.4110/in.2023.23.e6
Am J Physiol Lung Cell Mol Physiol. 2023 Mar 15.

Inhibition of glutaminase 1 activity reverses airway hyperresponsiveness and decreases IL-1β+ M1s and IL-17 producing ILC3s in high-fat diet-fed obese mice.

Ji-Su Shim, Hyun-Seung Lee, Hyuktae Kwon, Min-Hye Kim, Young-Joo Cho, Heung-Woo Park.

  In obesity, disturbed glutamine metabolism contributes to enhanced inflammation by inducing alterations in immune cells. As macrophages and innate lymphoid cells (ILCs) are known to be involved in the pathogenesis of obesity-related asthma, we tested our hypothesis that altered glutamine metabolism may link obesity to airway hyperresponsivenss (AHR), a cardinal feature of asthma, focusing on these innate immune cells. Four-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 13 weeks in the presence or absence of BPTES [Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, a selective inhibitor of glutaminase 1 which converts glutamine to glutamate] and their blood, lung, and adipose tissues were analyzed. We then conducted in vitro experiments using bone marrow-derived macrophages (BMDMs) and mouse alveolar macrophage cell line. Furthermore, we investigated plasma glutamine and glutamate levels in obese and non-obese asthmatics. BPTES treatment prevented HFD-induced AHR and significantly decreased IL-1β+ classically activated macrophages (M1s) and type 3 ILC (ILC3s) which increased in the lungs of HFD-fed obese mice. In in vitro experiments, BPTES treatment or glutamine supplement significantly reduced the proportion of IL-1β+NLRP3+ M1s in lipopolysaccharide-stimulated BMDMs and mouse alveolar macrophage cell line. BPTES treatment also significantly reduced the IL-17 producing ILC3s differentiated from ILCs in naïve mouse lung. In addition, plasma glutamate/glutamine ratios were significantly higher in obese asthmatics compared to non-obese asthmatics. Inhibition of glutaminolysis reverses AHR in HFD-induced obese mice and decreases IL-1β+NLRP3+ M1s and IL-17 producing ILC3s, which suggests altered glutamine metabolism may have a role in the pathogenesis of obesity-related AHR.

Keywords:  asthma; glutamine; innate lymphoid cells; macrophages; obesity

DOI:  https://doi.org/10.1152/ajplung.00181.2022
Int Immunopharmacol. 2023 Mar 15. pii: S1567-5769(23)00266-7. [Epub ahead of print]118 109946

Immunometabolomics provides a new perspective for studying systemic lupus erythematosus.

Yuxian Wu, Mengpei Zhao, Na Gong, Feng Zhang, Wansheng Chen, Yaoyang Liu.

  Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease characterized by clinical heterogeneity, unpredictable progression, and flare ups. Due to the heterogeneous nature of lupus, it has been challenging to identify sensitive and specific biomarkers for its diagnosis and monitoring. Despite the fact that the mechanism of SLE remains unknown, impressive progress has been made over the last decade towards understanding how different immune cells contribute to its pathogenesis. Research suggests that cellular metabolic programs could affect the immune response by regulating the activation, proliferation, and differentiation of innate and adaptive immune cells. Many studies have shown that the dysregulation of the immune system is associated with changes to metabolite profiles. The study of metabolite profiling may provide a means for mechanism exploration and novel biomarker discovery for disease diagnostic, classification, and monitoring. Here we review the latest advancements in understanding the role of immunometabolism in SLE, as well as the systemic metabolite profiling of this disease along with possible clinical application.

Keywords:  Biomarker; Diagnosis; Immunometabolomics; Metabolomics; SLE; Treatment

DOI:  https://doi.org/10.1016/j.intimp.2023.109946
J Clin Invest. 2023 Mar 15. pii: e169986. [Epub ahead of print]133(6):

UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis.

Jong-Seok Moon, Seonmin Lee, Mi-Ae Park, Ilias I Siempos, Maria Haslip, Patty J Lee, Mijin Yun, Chun K Kim, Judie Howrylak, Stefan W Ryter, Kiichi Nakahira, Augustine Mk Choi.

DOI: https://doi.org/10.1172/JCI169986
STAR Protoc. 2023 Mar 17. pii: S2666-1667(23)00133-8. [Epub ahead of print]4(2): 102175

High-content assay to measure mitochondrial function and bacterial vacuole size in infected human primary macrophages.

Mariatou Dramé, Francisco Javier Garcia-Rodriguez, Carmen Buchrieser, Pedro Escoll.

  Regulation of bioenergetics and cell death are pivotal mitochondrial functions determining the responses of macrophages to infection. Here, we provide a protocol to investigate mitochondrial functions during infection of macrophages by intracellular bacteria. We describe steps for quantifying mitochondrial polarization, cell death, and bacterial infection in infected, living, human primary macrophages at the single-cell level. We also detail the use of the pathogen Legionella pneumophila as model. This protocol can be adapted to investigate mitochondrial functions in other settings. For complete details on the use and execution of this protocol, please refer to Escoll et al. (2021).1.

Keywords:  Cell Biology; Cell-based Assays; High-throughput Screening; Immunology; Metabolism; Microbiology; Microscopy; Single Cell

DOI:  https://doi.org/10.1016/j.xpro.2023.102175
Front Immunol. 2023 ;14 1101433

Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells.

Laura Barbieri, Pedro Veliça, Paulo A Gameiro, Pedro P Cunha, Iosifina P Foskolou, Eric Rullman, David Bargiela, Randall S Johnson, Helene Rundqvist.

  Introduction: CD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in local tissues can result in significant exposure of cytotoxic T cells to the lactate metabolite. Lactate has been known to act as an immunosuppressor, at least in part due to its association with tissue acidosis.Methods: To dissect the role of the lactate anion, independently of pH, we performed phenotypical and metabolic assays, high-throughput RNA sequencing, and mass spectrometry, on primary cultures of murine or human CD8+ T cells exposed to high doses of pH-neutral sodium lactate.
Results: The lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and can displace glucose as a carbon source. Activation in the presence of sodium lactate significantly alters the CD8+ T cell transcriptome, including the expression key effector differentiation markers such as granzyme B and interferon-gamma.
Discussion: Our studies reveal novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.

Keywords:  CD8+ T cells; lactate; metabolism; oxygen; transcriptome

DOI:  https://doi.org/10.3389/fimmu.2023.1101433
Immunol Cell Biol. 2023 Mar 14.

Metabolic regulation of the circadian clock in classically and alternatively activated macrophages.

Petra Honzlová, Alena Sumová.

  Macrophages exhibit a range of functional pro- and anti-inflammatory states that induce changes in their cellular metabolism. We aimed to elucidate whether these changes affect the molecular properties of their circadian clock focusing on their anti-inflammatory phenotype. Primary cell cultures of bone marrow-derived macrophages (non-polarized M0 BMDM) from PER2::LUC mice were polarized into the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype, and PER2-driven bioluminescence was recorded in real-time at the cell-population and single-cell levels. Viability, clock gene expression profiles, polarization plasticity and PPARγ protein levels were analyzed. The effects of pharmacological activation/inhibition of PPARγ (Rosiglitazone/GW9662) and inhibition of fatty acid oxidation (FAO) by Etomoxir in M2 BMDM cell cultures were examined. The parameters of PER2-driven bioluminescence rhythms differed between M0, M1 and M2 BMDM cultures at cell population and single-cell levels. Compared with M0, polarization to M2 did not change the period but increased amplitude, mean bioluminescence level and rhythm persistence. Polarization to M1 shortened the period but had no effect on the amplitude of the rhythm. The same period changes were observed after a bidirectional switch between M1 and M2 polarized states in the same culture. Both PPARγ activation/inhibition and FAO inhibition modulated the clock in M2 BMDM, suggesting metabolic regulation of the M2 clock. Our results indicate that bidirectional changes in the properties of BMDM circadian clocks in response to their actual polarization are mediated via changes in their metabolic state. They provide new information on the interrelationship between the BMDM polarization, their circadian clock and cellular metabolism.

Keywords:  Etomoxir; GW9662; PPARγ; Rosiglitazone; circadian clock; macrophage; polarization

DOI:  https://doi.org/10.1111/imcb.12640
Front Immunol. 2023 ;14 1125594

The effect of sodium thiosulfate on immune cell metabolism during porcine hemorrhage and resuscitation.

Eva-Maria Wolfschmitt, Melanie Hogg, Josef Albert Vogt, Fabian Zink, Ulrich Wachter, Felix Hezel, Xiaomin Zhang, Andrea Hoffmann, Michael Gröger, Clair Hartmann, Holger Gässler, Thomas Datzmann, Tamara Merz, Andreas Hellmann, Christine Kranz, Enrico Calzia, Peter Radermacher, David Alexander Christian Messerer.

  Introduction: Sodium thiosulfate (Na2S2O3), an H2S releasing agent, was shown to be organ-protective in experimental hemorrhage. Systemic inflammation activates immune cells, which in turn show cell type-specific metabolic plasticity with modifications of mitochondrial respiratory activity. Since H2S can dose-dependently stimulate or inhibit mitochondrial respiration, we investigated the effect of Na2S2O3 on immune cell metabolism in a blinded, randomized, controlled, long-term, porcine model of hemorrhage and resuscitation. For this purpose, we developed a Bayesian sampling-based model for 13C isotope metabolic flux analysis (MFA) utilizing 1,2-13C2-labeled glucose, 13C6-labeled glucose, and 13C5-labeled glutamine tracers.Methods: After 3 h of hemorrhage, anesthetized and surgically instrumented swine underwent resuscitation up to a maximum of 68 h. At 2 h of shock, animals randomly received vehicle or Na2S2O3 (25 mg/kg/h for 2 h, thereafter 100 mg/kg/h until 24 h after shock). At three time points (prior to shock, 24 h post shock and 64 h post shock) peripheral blood mononuclear cells (PBMCs) and granulocytes were isolated from whole blood, and cells were investigated regarding mitochondrial oxygen consumption (high resolution respirometry), reactive oxygen species production (electron spin resonance) and fluxes within the metabolic network (stable isotope-based MFA).
Results: PBMCs showed significantly higher mitochondrial O2 uptake and lower O 2 • - production in comparison to granulocytes. We found that in response to Na2S2O3 administration, PBMCs but not granulocytes had an increased mitochondrial oxygen consumption combined with a transient reduction of the citrate synthase flux and an increase of acetyl-CoA channeled into other compartments, e.g., for lipid biogenesis.
Conclusion: In a porcine model of hemorrhage and resuscitation, Na2S2O3 administration led to increased mitochondrial oxygen consumption combined with stimulation of lipid biogenesis in PBMCs. In contrast, granulocytes remained unaffected. Granulocytes, on the other hand, remained unaffected. O 2 • - concentration in whole blood remained constant during shock and resuscitation, indicating a sufficient anti-oxidative capacity. Overall, our MFA model seems to be is a promising approach for investigating immunometabolism; especially when combined with complementary methods.

Keywords:  hemorrhagic shock; hydrogen sulfide; immunometabolism; innate immunity; metabolic flux analysis; metabolic modeling; mitochondrial respiration; reactive oxygen species

DOI:  https://doi.org/10.3389/fimmu.2023.1125594
Nat Commun. 2023 Mar 16. 14(1): 1459

Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis.

Pravin Kesarwani, Shiva Kant, Yi Zhao, Antony Prabhu, Katie L Buelow, C Ryan Miller, Prakash Chinnaiyan.

There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. A majority of this work has focused on the upstream metabolism of tryptophan; however, this has resulted in limited clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and demonstrate its critical role in promoting immune tolerance. QA acts as a metabolic checkpoint in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling in macrophages, resulting in a tumor supportive phenotype. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing immune modulatory agents to further clinical gains in these otherwise incurable diseases.

DOI: https://doi.org/10.1038/s41467-023-37170-z
bioRxiv. 2023 Mar 01. pii: 2023.02.28.530445. [Epub ahead of print]

HIV-differentiated metabolite N-Acetyl-L-Alanine dysregulates human natural killer cell responses to Mycobacterium tuberculosis infection.

Baojun Yang, Tanmoy Mukherjee, Rajesh Radhakrishnan, Padmaja Paidipally, Danish Ansari, Sahana John, Ramakrishna Vankayalapati, Deepak Tripathi, Guohua Yi.

Background: Mycobacterium tuberculosis ( Mtb ) has latently infected over two billion people worldwide (LTBI) and causes 1.8 million deaths each year. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of developing active tuberculosis by 10-20 times compared to the HIV-LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals.Methods: Plasma samples collected from healthy and HIV-infected individuals were investigated by liquid chromatography-mass spectrometry (LC-MS), and the metabolic data were analyzed using an online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, quantitative reverse transcription PCR (qRT-PCR) were performed by standard procedure to determine the surface markers, cytokines and other signaling molecule expression. Seahorse extra cellular flux assays were used to measure the mitochondrial oxidative phosphorylation and glycolysis.
Results: Six metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared to healthy donors. One of the HIV-upregulated metabolites, N-Acetyl-L-Alanine (ALA), inhibits pro-inflammatory cytokine IFN-□ production by NK cells of LTBI+ individuals. ALA inhibits glycolysis of LTBI+ individuals' NK cells in response to Mtb .
Conclusions: Our findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK cell-mediated immune responses to Mtb infection, offering a new understanding of the HIV- Mtb interaction and providing the implication of nutrition intervention and therapy for HIV- Mtb co-infected patients.

DOI: https://doi.org/10.1101/2023.02.28.530445
J Clin Invest. 2023 Mar 15. pii: e168366. [Epub ahead of print]133(6):

The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids.

Yoann Rombouts, Olivier Neyrolles.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipid-laden foamy macrophages that are a primary source of tissue destruction in patients with TB. In this issue of the JCI, Bedard et al. demonstrate that 1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis, caused lysosomal dysfunction associated with lipid storage in the phagolysosome of macrophages in a manner that mimicked lysosomal storage diseases. This work sheds light on how M. tuberculosis manipulates host lipid metabolism for its survival and opens avenues toward host-directed therapy against TB.

DOI: https://doi.org/10.1172/JCI168366
Neural Regen Res. 2023 Sep;18(9): 1946-1947

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Lige Leng, Jie Zhang.

DOI: https://doi.org/10.4103/1673-5374.367842
Res Sq. 2023 Feb 27. pii: rs.3.rs-2612547. [Epub ahead of print]

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

Emily Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.

Background: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyperresponsiveness to pathogens and neurodegeneration. Methods: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. Results: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. Conclusions: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.

DOI: https://doi.org/10.21203/rs.3.rs-2612547/v1
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00028-X. [Epub ahead of print]83(6): 1012-1012.e1

SnapShot: Mitochondrial signaling.

Taylor A Poor, Navdeep S Chandel.

Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.molcel.2023.01.008
Mol Cancer Ther. 2023 Mar 13. pii: MCT-22-0431. [Epub ahead of print]

Novel arginase inhibitor, AZD0011, demonstrates immune cell stimulation and anti-tumor efficacy with diverse combination partners.

Aatman S Doshi, Susan Cantin, Marylens Hernandez, Srimathi Srinivasan, Sharon Tentarelli, Matthew Griffin, Yanjun Wang, Petar Pop-Damkov, Laura B Prickett, Cecilia Kankkonen, Minhui Shen, Maryann San Martin, Song Wu, M Paola Castaldi, Hormas Ghadially, Jeffrey Varnes, Sonya Gales, David Henry, Clare Hoover, Deanna A Mele, Iain Simpson, Eric T Gangl, Scott N Mlynarski, M Raymond V Finlay, Lisa Drew, Stephen E Fawell, Wenlin Shao, Alwin G Schuller.

Anti-tumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment including recruitment of arginase (ARG) expressing myeloid cells which deplete L-arginine essential for optimal T cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing anti-tumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition (TGI) in various syngeneic models. Anti-tumor responses increase when AZD0011 is combined with anti-PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti-PD-L1 and anti-NKG2A, and combination benefits with type I interferon (IFN) inducers including polyI:C and radiation. Our pre-clinical data demonstrates AZD0011's ability to reverse tumor immunosuppression and enhance immune stimulation and anti-tumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.

DOI: https://doi.org/10.1158/1535-7163.MCT-22-0431
Virulence. 2023 Mar 13. 2190645

The F1Fo-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism.

Shuixiu Li, Yuting Liu, Luobei Weng, Yajing Zhao, Yishan Zhang, Zhanpeng Zhang, Yang Yang, Qiaoxin Chen, Xiaochong Liu, Hong Zhang.

  Sepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F1Fo-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F1Fo-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F1Fo-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1β, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F1Fo-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F1Fo-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F1Fo-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F1Fo-ATP synthase α subunit activity to control the induction of host inflammatory responses.

Keywords:  Candida albicans; F1Fo-ATP synthase; amino acid catabolism; inflammatory response; α subunit

DOI:  https://doi.org/10.1080/21505594.2023.2190645
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00149-1. [Epub ahead of print]83(6): 829-831

HK2: Gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions.

Jing Fang, Shudi Luo, Zhimin Lu.

Hexokinase 2 (HK2) plays a multifaceted role in the regulation of cellular activities. A new study by Hu et al.1 delineated a critical role of HK2 in governing glycolytic flux and mitochondrial activity, thereby modulating microglial functions in maladaptive inflammation in brain diseases.

DOI: https://doi.org/10.1016/j.molcel.2023.02.022
Redox Biol. 2023 Mar 08. pii: S2213-2317(23)00062-9. [Epub ahead of print]62 102661

Cholesterol confers ferroptosis resistance onto myeloid-biased hematopoietic stem cells and prevents irradiation-induced myelosuppression.

Chaonan Liu, Weinian Liao, Jun Chen, Kuan Yu, Yiding Wu, Shuzhen Zhang, Mo Chen, Fang Chen, Song Wang, Tianmin Cheng, Junping Wang, Changhong Du.

  There is growing appreciation that hematopoietic alterations underpin the ubiquitous detrimental effects of metabolic disorders. The susceptibility of bone marrow (BM) hematopoiesis to perturbations of cholesterol metabolism is well documented, while the underlying cellular and molecular mechanisms remain poorly understood. Here we reveal a distinct and heterogeneous cholesterol metabolic signature within BM hematopoietic stem cells (HSCs). We further show that cholesterol directly regulates maintenance and lineage differentiation of long-term HSCs (LT-HSCs), with high levels of intracellular cholesterol favoring maintenance and myeloid bias of LT-HSCs. During irradiation-induced myelosuppression, cholesterol also safeguards LT-HSC maintenance and myeloid regeneration. Mechanistically, we unravel that cholesterol directly and distinctively enhances ferroptosis resistance and boosts myeloid but dampens lymphoid lineage differentiation of LT-HSCs. Molecularly, we identify that SLC38A9-mTOR axis mediates cholesterol sensing and signal transduction to instruct lineage differentiation of LT-HSCs as well as to dictate ferroptosis sensitivity of LT-HSCs through orchestrating SLC7A11/GPX4 expression and ferritinophagy. Consequently, myeloid-biased HSCs are endowed with a survival advantage under both hypercholesterolemia and irradiation conditions. Importantly, a mTOR inhibitor rapamycin and a ferroptosis inducer imidazole ketone erastin prevent excess cholesterol-induced HSC expansion and myeloid bias. These findings unveil an unrecognized fundamental role of cholesterol metabolism in HSC survival and fate decisions with valuable clinical implications.

Keywords:  Cholesterol; Ferroptosis; Hematopoietic stem cell; Ionizing radiation; Myeloid bias; Myelosuppression

DOI:  https://doi.org/10.1016/j.redox.2023.102661
Nat Rev Immunol. 2023 Mar 15.

Tissue-specific macrophages: how they develop and choreograph tissue biology.

Elvira Mass, Falk Nimmerjahn, Katrin Kierdorf, Andreas Schlitzer.

Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other waste products. Simultaneously, they produce growth factors and signalling molecules - such activities not only promote host protection in response to invading microorganisms but are also crucial for organ development and homeostasis. There is mounting evidence of macrophages orchestrating fundamental physiological processes, such as blood vessel formation, adipogenesis, metabolism and central and peripheral neuronal function. In parallel, novel methodologies have led to the characterization of tissue-specific macrophages, with distinct subpopulations of these cells showing different developmental trajectories, transcriptional programmes and life cycles. Here, we summarize our growing knowledge of macrophage diversity and how macrophage subsets orchestrate tissue development and function. We further interrelate macrophage ontogeny with their core functions across tissues, that is, the signalling events within the macrophage niche that may control organ functionality during development, homeostasis and ageing. Finally, we highlight the open questions that will need to be addressed by future studies to better understand the tissue-specific functions of distinct macrophage subsets.

DOI: https://doi.org/10.1038/s41577-023-00848-y