bims-imicid 2022-12-11 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒12‒11
thirty-two papers selected by
Dylan Ryan
University of Cambridge

Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles.
LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.
The circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing.
The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli.
Innate antiviral immunity and immunometabolism in hepatocytes.
HIV-1 replication and latency are balanced by mTOR-driven cell metabolism.
Myeloid-Derived Itaconate Suppresses Antitumor Immunity.
Age-associated remodeling of T cell immunity and metabolism.
Glutamine Metabolism Supports the Functional Activity of Immune Cells against Aspergillus fumigatus.
Glucose metabolism is upregulated in the mononuclear cell proteome during sepsis and supports endotoxin-tolerant cell function.
Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism.
Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.
The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
GABA regulates IL-1β production in macrophages.
Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.
What role for cellular metabolism in the control of hepatitis viruses?
Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.
Memory CD8+ T cells upregulate glycolysis and effector functions under limiting oxygen conditions.
Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever.
The tumor microenvironment drives NK cell metabolic dysfunction leading to impaired anti-tumor activity.
Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression.
Tuberous Sclerosis Complex 1 Deficiency in Macrophages Promotes Unclassical Inflammatory Response to Lipopolysaccharide In Vitro and Dextran Sodium Sulfate-Induced Colitis in Mice.
Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.
Immune-metabolic adaptations in pregnancy: A potential stepping-stone to sepsis.
Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity.
Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit.
Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-responders.
Microbiome-derived metabolites counteract tumor-induced immunosuppression and boost immune checkpoint blockade.
Tetrahydroxy Stilbene Glucoside Alleviates Ischemic Stroke by Regulating Conformation-Dependent Intracellular Distribution of PKM2 for M2 Macrophage Polarization.
Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor.
Plant-cell machinery for making metabolites transferred to mammalian cells.
A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.

Nat Immunol. 2022 Dec 05.

Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles.

Ke Tang, Huafeng Zhang, Jinghui Deng, Dianheng Wang, Shichuan Liu, Shuya Lu, Qingfa Cui, Chen Chen, Jincheng Liu, Zhuoshun Yang, Yonggang Li, Jie Chen, Jiadi Lv, Jingwei Ma, Bo Huang.

Amino acid metabolism is essential for cell survival, while the byproduct ammonia is toxic and can injure cellular longevity. Here we show that CD8+ memory T (TM) cells mobilize the carbamoyl phosphate (CP) metabolic pathway to clear ammonia, thus promoting memory development. CD8+ TM cells use β-hydroxybutyrylation to upregulate CP synthetase 1 and trigger the CP metabolic cascade to form arginine in the cytosol. This cytosolic arginine is then translocated into the mitochondria where it is split by arginase 2 to urea and ornithine. Cytosolic arginine is also converted to nitric oxide and citrulline by nitric oxide synthases. Thus, both the urea and citrulline cycles are employed by CD8+ T cells to clear ammonia and enable memory development. This ammonia clearance machinery might be targeted to improve T cell-based cancer immunotherapies.

DOI: https://doi.org/10.1038/s41590-022-01365-1
Nat Cell Biol. 2022 Dec;24(12): 1701-1713

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.

Ryan M Allen, Danielle L Michell, Ashley B Cavnar, Wanying Zhu, Neil Makhijani, Danielle M Contreras, Chase A Raby, Elizabeth M Semler, Carlisle DeJulius, Mark Castleberry, Youmin Zhang, Marisol Ramirez-Solano, Shilin Zhao, Craig Duvall, Amanda C Doran, Quanhu Sheng, MacRae F Linton, Kasey C Vickers.

Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.

DOI: https://doi.org/10.1038/s41556-022-01030-7
Nat Commun. 2022 Dec 05. 13(1): 7217

The circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing.

Mariana P Cervantes-Silva, Richard G Carroll, Mieszko M Wilk, Diana Moreira, Cloe A Payet, James R O'Siorain, Shannon L Cox, Lauren E Fagan, Paula A Klavina, Yan He, Tabea Drewinski, Alan McGinley, Sharleen M Buel, George A Timmons, James O Early, Roger J S Preston, Jennifer M Hurley, David K Finlay, Ingmar Schoen, F Javier Sánchez-García, Kingston H G Mills, Annie M Curtis.

Dendritic cells play a key role in processing and presenting antigens to naïve T cells to prime adaptive immunity. Circadian rhythms are known to regulate many aspects of immunity; however, the role of circadian rhythms in dendritic cell function is still unclear. Here, we show greater T cell responses when mice are immunised in the middle of their rest versus their active phase. We find a circadian rhythm in antigen processing that correlates with rhythms in both mitochondrial morphology and metabolism, dependent on the molecular clock gene, Bmal1. Using Mdivi-1, a compound that promotes mitochondrial fusion, we are able to rescue the circadian deficit in antigen processing and mechanistically link mitochondrial morphology and antigen processing. Furthermore, we find that circadian changes in mitochondrial Ca2+ are central to the circadian regulation of antigen processing. Our results indicate that rhythmic changes in mitochondrial calcium, which are associated with changes in mitochondrial morphology, regulate antigen processing.

DOI: https://doi.org/10.1038/s41467-022-34897-z
mBio. 2022 Dec 08. e0306822

The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli.

Bevin C English, Hannah P Savage, Scott P Mahan, Vladimir E Diaz-Ochoa, Briana M Young, Basel H Abuaita, Gautam Sule, Jason S Knight, Mary X O'Riordan, Andreas J Bäumler, Renée M Tsolis.

  Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the endoplasmic reticulum (ER) stress sensor Inositol-requiring enzyme 1 alpha (IRE1α) and its downstream transcription factor X box binding protein 1 (XBP1) enhance the upregulation of glycolysis in classically activated macrophages (CAMs). The IRE1α-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by lipopolysaccharide (LPS) stimulation or infection with the intracellular bacterial pathogen Brucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1α activation; while Toll-like receptor 4 (TLR4) supports glycolysis under both conditions, TLR4 is required for activation of IRE1α in response to LPS treatment but not B. abortus infection. Though IRE1α and XBP1 are necessary for maximal induction of glycolysis in CAMs, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cell's metabolic response and that IRE1α activation may be a way to fine-tune metabolic reprogramming. IMPORTANCE The immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1α, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection with Brucella abortus or challenge with Salmonella LPS. Interestingly, these stimuli activate IRE1α by independent mechanisms. While the IRE1α-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1α and XBP1 in innate immunity.

Keywords:  Brucella; endoplasmic reticulum; immunometabolism; innate immunity

DOI:  https://doi.org/10.1128/mbio.03068-22
Curr Opin Immunol. 2022 Nov 29. pii: S0952-7915(22)00114-5. [Epub ahead of print]80 102267

Innate antiviral immunity and immunometabolism in hepatocytes.

Vasile Mihai Sularea, Jamie A Sugrue, Cliona O'Farrelly.

The human liver mediates whole-body metabolism, systemic inflammation and responses to hepatotropic pathogens. Hepatocytes, the most abundant cell type of the liver, have critical roles in each of these activities. The regulation of metabolic pathways, such as glucose metabolism, lipid biosynthesis and oxidation, influences whole-organism functionality. However, the immune potential of the liver in general and hepatocytes in particular is also determined by metabolic ability. The major shifts in cellular metabolism required to drive activity in immune cells are now well-described. Given the unique functions of hepatocytes in systemic metabolism and inflammation, and their ability to mediate local antiviral innate immunity, the metabolic shifts required to facilitate these activities are likely to be complex and challenging to define. In this review, we explore what is known about the complex metabolic rewiring required for hepatocytes to respond appropriately to viral infection. We also discuss how viruses can manipulate hepatocyte metabolism to facilitate infection.

DOI: https://doi.org/10.1016/j.coi.2022.102267
Front Cell Infect Microbiol. 2022 ;12 1068436

HIV-1 replication and latency are balanced by mTOR-driven cell metabolism.

Jacqueline M Crater, Douglas F Nixon, Robert L Furler O'Brien.

  Human Immunodeficiency virus type 1 (HIV-1) relies on host cell metabolism for all aspects of viral replication. Efficient HIV-1 entry, reverse transcription, and integration occurs in activated T cells because HIV-1 proteins co-opt host metabolic pathways to fuel the anabolic requirements of virion production. The HIV-1 viral life cycle is especially dependent on mTOR, which drives signaling and metabolic pathways required for viral entry, replication, and latency. As a central regulator of host cell metabolism, mTOR and its downstream effectors help to regulate the expression of enzymes within the glycolytic and pentose phosphate pathways along with other metabolic pathways regulating amino acid uptake, lipid metabolism, and autophagy. In HIV-1 pathogenesis, mTOR, in addition to HIF-1α and Myc signaling pathways, alter host cell metabolism to create an optimal environment for viral replication. Increased glycolysis and pentose phosphate pathway activity are required in the early stages of the viral life cycle, such as providing sufficient dNTPs for reverse transcription. In later stages, fatty acid synthesis is required for creating cholesterol and membrane lipids required for viral budding. Epigenetics of the provirus fueled by metabolism and mTOR signaling likewise controls active and latent infection. Acetyl-CoA and methyl group abundance, supplied by the TCA cycle and amino acid uptake respectively, may regulate latent infection and reactivation. Thus, understanding and exploring new connections between cellular metabolism and HIV-1 pathogenesis may yield new insights into the latent viral reservoirs and fuel novel treatments and cure strategies.

Keywords:  CD4 + T cell; HIV-1; glycolysis; immunometabolism; mTOR

DOI:  https://doi.org/10.3389/fcimb.2022.1068436
Cancer Discov. 2022 Dec 09. OF1

Myeloid-Derived Itaconate Suppresses Antitumor Immunity.

Itaconate secreted by MDSCs suppresses CD8+ T-cell effector function and promotes tumor growth.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-213
Cell Metab. 2022 Nov 29. pii: S1550-4131(22)00496-X. [Epub ahead of print]

Age-associated remodeling of T cell immunity and metabolism.

SeongJun Han, Peter Georgiev, Alison E Ringel, Arlene H Sharpe, Marcia C Haigis.

  Aging results in remodeling of T cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this review, we summarize recent advances in our understanding of aged T cell metabolism, with a focus on the bioenergetic and immunologic features of T cell subsets unique to the aging process. We also survey insights into mechanisms of metabolic T cell dysfunction in aging and discuss the impacts of aging on the efficacy of cancer immunotherapy. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T cell immunity will be instrumental for the development of therapeutic strategies for older patients.

Keywords:  T cells; aging; cancer; immunity; immunotherapy; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2022.11.005
Microbiol Spectr. 2022 Dec 08. e0225622

Glutamine Metabolism Supports the Functional Activity of Immune Cells against Aspergillus fumigatus.

Daniela Antunes, Samuel M Gonçalves, Vasiliki Matzaraki, Cláudia S Rodrigues, Relber A Gonçales, Joana Rocha, Jorge Sáiz, António Marques, Egídio Torrado, Ricardo Silvestre, Fernando Rodrigues, Frank L van de Veerdonk, Coral Barbas, Mihai G Netea, Vinod Kumar, Cristina Cunha, Agostinho Carvalho.

  The reprogramming of cellular metabolism of immune cells is an essential process in the regulation of antifungal immune responses. In particular, glucose metabolism has been shown to be required for protective immunity against infection with Aspergillus fumigatus. However, given the intricate cross talk between multiple metabolic networks and signals, it is likely that cellular metabolic pathways other than glycolysis are also relevant during fungal infection. In this study, we demonstrate that glutamine metabolism is required for the activation of macrophage effector functions against A. fumigatus. Glutamine metabolism was found to be upregulated early after fungal infection and glutamine depletion or the pharmacological inhibition of enzymes involved in its metabolism impaired phagocytosis and the production of both proinflammatory and T-cell-derived cytokines. In an in vivo model, inhibition of glutaminase increased susceptibility to experimental aspergillosis, as revealed by the increased fungal burden and inflammatory pathology, and the defective cytokine production in the lungs. Moreover, genetic variants in glutamine metabolism genes were found to regulate cytokine production in response to A. fumigatus stimulation. Taken together, our results demonstrate that glutamine metabolism represents an important component of the immunometabolic response of macrophages against A. fumigatus both in vitro and in vivo. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. The reprogramming of cellular metabolism is essential for innate immune cells to mount effective antifungal responses. In this study, we report the pivotal contribution of glutaminolysis to the host defense against A. fumigatus. Glutamine metabolism was essential both in vitro as well as in in vivo models of infection, and genetic variants in human glutamine metabolism genes regulated cytokine production in response to fungal stimulation. This work highlights the relevance of glutaminolysis to the pathogenesis of aspergillosis and supports a role for interindividual genetic variation influencing glutamine metabolism in susceptibility to infection.

Keywords:  Aspergillus; antifungal immunity; glutamine; immunometabolism; macrophage

DOI:  https://doi.org/10.1128/spectrum.02256-22
Front Immunol. 2022 ;13 1051514

Glucose metabolism is upregulated in the mononuclear cell proteome during sepsis and supports endotoxin-tolerant cell function.

Bianca Lima Ferreira, Mônica Bragança Sousa, Giuseppe Gianini Figueirêdo Leite, Milena Karina Colo Brunialti, Erika Sayuri Nishiduka, Alexandre Keiji Tashima, Tom van der Poll, Reinaldo Salomão.

  Metabolic adaptations shape immune cell function. In the acute response, a metabolic switch towards glycolysis is necessary for mounting a proinflammatory response. During the clinical course of sepsis, both suppression and activation of immune responses take place simultaneously. Leukocytes from septic patients present inhibition of cytokine production while other functions such as phagocytosis and production of reactive oxygen species (ROS) are preserved, similarly to the in vitro endotoxin tolerance model, where a first stimulation with lipopolysaccharide (LPS) affects the response to a second stimulus. Here, we sought to investigate how cellular metabolism is related to the modulation of immune responses in sepsis and endotoxin tolerance. Proteomic analysis in peripheral blood mononuclear cells (PBMCs) from septic patients obtained at intensive care unit admission showed an upregulation of proteins related to glycolysis, the pentose phosphate pathway (PPP), production of ROS and nitric oxide, and downregulation of proteins in the tricarboxylic acid cycle and oxidative phosphorylation compared to healthy volunteers. Using the endotoxin-tolerance model in PBMCs from healthy subjects, we observed increased lactate production in control cells upon LPS stimulation, while endotoxin-tolerant cells presented inhibited tumor necrosis factor-α and lactate production along with preserved phagocytic capacity. Inhibition of glycolysis and PPP led to impairment of phagocytosis and cytokine production both in control and in endotoxin-tolerant cells. These data indicate that glucose metabolism supports leukocyte functions even in a condition of endotoxin tolerance.

Keywords:  LPS; PBMCs; endotoxin-tolerance; glycolysis; immunometabolism; pentose phosphate pathway; sepsis

DOI:  https://doi.org/10.3389/fimmu.2022.1051514
Front Oncol. 2022 ;12 1042196

Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism.

Shadia Hamoud Alshahrani, Yousif Saleh Ibrahim, Abduladheem Turki Jalil, Abdelgadir Alamin Altoum, Harun Achmad, Rahman S Zabibah, Gamal A Gabr, Andrés Alexis Ramírez-Coronel, Ameer A Alameri, Qutaiba A Qasim, Sajad Karampoor, Rasoul Mirzaei.

  MicroRNAs (miRNAs) are emerging as a significant modulator of immunity, and their abnormal expression/activity has been linked to numerous human disorders, such as cancer. It is now known that miRNAs potentially modulate the production of several metabolic processes in tumor-associated immune cells and indirectly via different metabolic enzymes that affect tumor-associated signaling cascades. For instance, Let-7 has been identified as a crucial modulator for the long-lasting survival of CD8+ T cells (naive phenotypes) in cancer by altering their metabolism. Furthermore, in T cells, it has been found that enhancer of zeste homolog 2 (EZH2) expression is controlled via glycolytic metabolism through miRNAs in patients with ovarian cancer. On the other hand, immunometabolism has shown us that cellular metabolic reactions and processes not only generate ATP and biosynthetic intermediates but also modulate the immune system and inflammatory processes. Based on recent studies, new and encouraging approaches to cancer involving the modification of miRNAs in immune cell metabolism are currently being investigated, providing insight into promising targets for therapeutic strategies based on the pivotal role of immunometabolism in cancer. Throughout this overview, we explore and describe the significance of miRNAs in cancer and immune cell metabolism.

Keywords:  MicroRNAs; cancer; immune cell; immunometabolism; metabolism

DOI:  https://doi.org/10.3389/fonc.2022.1042196
J Immunol. 2022 Dec 15. 209(12): 2287-2291

Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.

Chirag H Patel, Emily B Heikamp, Wei Xu, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Jiayu Wen, Ada J Tam, Richard L Blosser, Jonathan D Powell.

The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.

DOI: https://doi.org/10.4049/jimmunol.2100669
Front Immunol. 2022 ;13 1028953

The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.

Jessica Astorga, Naschla Gasaly, Karen Dubois-Camacho, Marjorie De la Fuente, Glauben Landskron, Klaas Nico Faber, Félix A Urra, Marcela A Hermoso.

  Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.

Keywords:  IBD - inflammatory bowel disease; NLRP3 inflammasome; diet phytochemicals; inflammasome; intracellular cholesterol accumulation; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fimmu.2022.1028953
Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01653-9. [Epub ahead of print]41(10): 111770

GABA regulates IL-1β production in macrophages.

Jian Fu, Ziyi Han, Zebiao Wu, Yaoyao Xia, Guan Yang, Yulong Yin, Wenkai Ren.

  Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrate that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-flavin adenine dinucleotide (FAD)-lysine specific demethylase1 (LSD1) signaling to regulate histone demethylation of Bcl2l11 and Dusp2, reducing formation of the NLRP3-ASC-Caspase-1 complex. The GABA-succinate axis reduces succinylation of mitochondrial proteins to promote oxidative phosphorylation (OXPHOS). We also find that GABA alleviates lipopolysaccharides (LPS)-induced sepsis as well as high-fat-diet-induced obesity in mice. Our study shows that GABA regulates pro-inflammatory macrophage responses associated with metabolic reprogramming and protein succinylation, suggesting a strategy for treating macrophage-related inflammatory diseases.

Keywords:  CP: Immunology; FAD; GABA; macrophage; succinate; succinylation

DOI:  https://doi.org/10.1016/j.celrep.2022.111770
Adv Sci (Weinh). 2022 Dec 07. e2204808

Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.

Junlong Zhao, Zhimin Tian, Shoujie Zhao, Dayun Feng, Zhixiong Guo, Liangzhi Wen, Yejing Zhu, Fenghua Xu, Jun Zhu, Shouzheng Ma, Jie Hu, Tao Jiang, Yongquan Qu, Dongfeng Chen, Lei Liu.

  Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

Keywords:  catalysis; immunotherapy; lactate; metabolism; tumor

DOI:  https://doi.org/10.1002/advs.202204808
Front Immunol. 2022 ;13 1033314

What role for cellular metabolism in the control of hepatitis viruses?

Olivier Diaz, Pierre-Olivier Vidalain, Christophe Ramière, Vincent Lotteau, Laure Perrin-Cocon.

  Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.

Keywords:  cellular metabolism; hepatitis virus; hepatocyte; immunometabolism; inflammation; innate immunity; liver diseases

DOI:  https://doi.org/10.3389/fimmu.2022.1033314
Oncogene. 2022 Dec 06.

Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.

Yuqing Yang, Lin Chen, Bohao Zheng, Shengtao Zhou.

Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.

DOI: https://doi.org/10.1038/s41388-022-02562-w
Eur J Immunol. 2022 Nov 22.

Memory CD8+ T cells upregulate glycolysis and effector functions under limiting oxygen conditions.

Ammarina Beumer-Chuwonpad, Floris P J van Alphen, Natasja A M Kragten, Julian J Freen-van Heeren, Maria Rodriguez Gomez, Arthur J Verhoeven, Maartje van den Biggelaar, Klaas P J M van Gisbergen.

  Memory CD8+ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence at oxygen-deprived infected tissue sites or in tumors, the impact of local oxygen pressure on memory CD8+ T cells remains largely unclear. We sought to elucidate how oxygen pressure impacts memory CD8+ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8+ T cell metabolism from oxidative phosphorylation to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8+ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN-γ production capacity. In vivo, memory CD8+ T cells cultured under low oxygen pressure provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8+ T cells with superior effector functions.

Keywords:  CD8+ memory T cells; Cytotoxic T cells; Hypoxic T cell cultures; T cell metabolism; glycolysis

DOI:  https://doi.org/10.1002/eji.202249918
EMBO Mol Med. 2022 Dec 07. e15931

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever.

Lisa Kohl, Md Nur A Alam Siddique, Barbara Bodendorfer, Raffaela Berger, Annica Preikschat, Christoph Daniel, Martha Ölke, Elisabeth Liebler-Tenorio, Jan Schulze-Luehrmann, Michael Mauermeir, Kai-Ting Yang, Inaya Hayek, Manuela Szperlinski, Jennifer Andrack, Ulrike Schleicher, Aline Bozec, Gerhard Krönke, Peter J Murray, Stefan Wirtz, Masahiro Yamamoto, Valentin Schatz, Jonathan Jantsch, Peter Oefner, Daniel Degrandi, Klaus Pfeffer, Katja Mertens-Scholz, Simon Rauber, Christian Bogdan, Katja Dettmer, Anja Lührmann, Roland Lang.

  Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis-aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1-/- mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1-/- mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1-/- mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.

Keywords:  Cis-aconitate decarboxylase 1; Coxiella burnetii; Immune responsive gene 1; immunometabolism; itaconate

DOI:  https://doi.org/10.15252/emmm.202215931
Int J Cancer. 2022 Dec 05.

The tumor microenvironment drives NK cell metabolic dysfunction leading to impaired anti-tumor activity.

Nicola Tumino, Carina B Nava Lauson, Silvia Tiberti, Francesca Besi, Stefania Martini, Piera Filomena Fiore, Francesca Scodamaglia, Maria Cristina Mingari, Lorenzo Moretta, Teresa Manzo, Paola Vacca.

  NK cells represent key players capable of driving anti-tumor immune responses. However, the potent immunosuppressive activity of the tumor microenvironment (TME) may impair their effector function. Here, we strengthen the importance of metabolic interactions between NK cells and TME and propose metabolic dysfunction as one of the major mechanisms behind NK failure in cancer treatment. In particular, we described that TME has a direct negative impact on NK cell function by disrupting their mitochondrial integrity and function in pediatric and adult patients with primary and metastatic cancer. Our results will help to design new strategies aimed at increasing the NK cell anti-tumor efficacy by their metabolic reprogramming. In this regard, we reveal an unprecedented role of IL15 in the metabolic reprogramming of NK cells enhancing their antitumor functions. IL15 prevents the inhibitory effect of soluble factors present in TME and restores both the metabolic characteristics and the effector function of NK cells inhibited by exposure to malignant pleural fluid. Thus, we propose here that IL15 may be exploited as a new strategy to metabolically reprogram NK cells with the aim of increasing the efficacy of NK-based immunotherapy in a wide range of currently refractory adult and pediatric solid tumors.

Keywords:  Metabolic Dysfunction; NK cells; Tumor Immunology; Tumor Microenviornment

DOI:  https://doi.org/10.1002/ijc.34389
Biochem Pharmacol. 2022 Dec 05. pii: S0006-2952(22)00464-6. [Epub ahead of print] 115369

Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression.

Srijan Dubey, Sayak Ghosh, Debosmita Goswami, Debapriya Ghatak, Rudranil De.

  Macrophages are specialized immune cells, which have the capacity to phagocytize and destroy the target cells, including tumor cells. Some macrophages, however on their way to devour the cancer cells undergo a change due to a complex set of signaling pathways. They are induced to change into a polarized state known as M2. The M2 macrophages help in metastasis, tumor suppression, and angiogenesis. The macrophage which gets associated with this TME, are referred to as tumor-associated macrophages (TAMs). TAMS undergo a metabolic reprogramming toward oxidative metabolism for bioenergetic purposes (OXPHOS), fatty acid oxidation (FAO), decreased glycolysis, decreased metabolism via the PPP, and upregulation of arginase 1 (ARG1) which triggers immunosuppressive pro-tumor signaling in the tumor microenvironment (TME) in which mitochondria plays an instrumental role. Reports have suggested that a complex series of interactions and exchange of materials, such as cytokines, metabolic intermediates and sometimes even transfer of mitochondria take place between TAMS and other TME components most importantly cancer cells that reprogram their metabolism to encourage cell growth, division, epithelial to mesenchymal transition, that ultimately play an important role in tumor progression. This review will try to focus on the crosstalk between the TAMs with several other components of TME, what instrumental role mitochondria play in that and also try to explore some of the therapeutic options available in cancer patients.

Keywords:  Macrophage polarization; Mitochondria; Tumor microenvironment; Tumor-Associated Macrophages; cytokines

DOI:  https://doi.org/10.1016/j.bcp.2022.115369
Aging Dis. 2022 Dec 01. 13(6): 1875-1890

Tuberous Sclerosis Complex 1 Deficiency in Macrophages Promotes Unclassical Inflammatory Response to Lipopolysaccharide In Vitro and Dextran Sodium Sulfate-Induced Colitis in Mice.

Huawen Xu, Yang Zhao, Qingjie Zhao, Mingpu Shi, Zhaoqi Zhang, Wenjun Ding, Yong Zhao.

  Human tuberous sclerosis (TSC) is mainly caused by genetic mutations of tuberous TSC1or TSC2. Recent studies found that TSC1 deficiency promoted classical M1 macrophage polarization. However, whether TSC1 regulates other inflammatory cytokine expression in lipopolysaccharidem (LPS)-stimulated macrophages is unknown. Herein, we studied the cytokine expression profile of wild-type (WT) and TSC1-deleted macrophages after LPS stimulation in vitro and the pathogenesis of dextran sodium sulfate (DSS)-induced colitis in mice with myeloid-specific TSC1 deletion (TSC1cKO mice). We found that TSC1-deficient macrophages exhibited the enhanced secretion of interleukin-17A (IL-17A), IL-17F, and interferon-gamma (IFN-γ) in response to LPS stimulation in vitro. This is in contrast to LPS-stimulated WT macrophages, which usually do not. Importantly, TSC1cKO mice exhibited exacerbated DSS-induced acute colitis with severer symptoms. MTOR deletion or rapamycin treatment significantly reversed the enhanced expressions of IL-17A, IL-17F, and IFN-γ in LPS-stimulated TSC1-deficient macrophages in vitro and rescued the enhanced DSS-induced colitis in TSC1cKO mice, indicating that TSC1 deficiency increased these cytokine productions in an mTOR-dependent manner. RNA-sequencing and molecular studies indicated that TSC1 deficiency enhanced the aerobic glycolysis process and the activities of mTOR-STAT3-RORγT pathway in LPS-stimulated macrophages. Inhibition of aerobic glycolysis, STAT3, or RORγT reversed IL-17 and IFN-γ expression in LPS-treated TSC1-deficient macrophages. Thus, TSC1 is essential for macrophages to shut down IL-17A, IL-17F, and IFN-γ expression during LPS stimulation by suppressing the aerobic glycolysis process and mTOR-STAT3, RORγT, and T-bet pathways. The present study uncovered the key role of TSC1 in shutting down IL-17A, IL-17F, and IFN-γ expressions in LPS-treated macrophages.

Keywords:  Tuberous sclerosis complex 1 (TSC1); colitis; inflammation; lipopolysaccharide; macrophage polarization; mammalian target of rapamycin (mtor)

DOI:  https://doi.org/10.14336/AD.2022.0408
J Clin Invest. 2022 Dec 08. pii: e159498. [Epub ahead of print]

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.

Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S Olson, Jennifer Davis, Rong Tian.

  Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found myeloid specific deletion of mitochondrial Complex I protein Ndufs4 (mKO) reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to lipopolysacharride. Moreover, mKO mice showed increased mortality, poor scar formation and worsened cardiac function 30 days post-MI. We observed a greater inflammatory response in mKO on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to reparative phase during day 3-7 post-MI. Efferocytosis is markedly impaired in mKO macrophages leading to lower expression of anti-inflammatory cytokine and tissue repair factors, which suppressed the proliferation/activation of myofibroblasts in the infarct area. Mitochondria-targeted ROS scavenging rescued these impairments and improved myofibroblast function in vivo and reduced post-MI mortality in mKO mice. Together these results reveal a novel role of mitochondria in inflammation resolution and tissue repair via modulating efferocytosis and crosstalk with fibroblasts. The findings are significant for post-MI recovery as well as for other inflammatory conditions.

Keywords:  Cardiology; Cardiovascular disease; Macrophages; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI159498
EBioMedicine. 2022 Nov 04. pii: S2352-3964(22)00519-9. [Epub ahead of print] 104337

Immune-metabolic adaptations in pregnancy: A potential stepping-stone to sepsis.

Simran Sharma, Patricia R S Rodrigues, Summia Zaher, Luke C Davies, Peter Ghazal.

  Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cellular, and molecular systems-level in the context of sepsis. We identify distinct immune phases in pregnancy delineated by placental hormone-driven changes in homeostasis setpoints of the immune and metabolic systems that subtly mirrors changes observed in sepsis. We propose that pregnancy immune-metabolic setpoint changes impact feedback thresholds that increase risk for a maladapted host-response to infection and thus act as a stepping-stone to sepsis. Defining maternal immune-metabolic setpoint changes is not only vital for tailoring the right diagnostic tools for early management of maternal sepsis but will facilitate an unravelling of the pathophysiological pathways that predispose an individual to sepsis.

Keywords:  Homeostasis; Hormones; Immunity; Maternal sepsis; Maternity; Metabolism; Pregnancy; Sepsis; Set-point change; Setpoint; Vaccines

DOI:  https://doi.org/10.1016/j.ebiom.2022.104337
Front Immunol. 2022 ;13 1004644

Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity.

Bandik Föh, Jana Sophia Buhre, Christian Sina, Marc Ehlers.

  The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic strategies. B cell-derived plasma cells are major players in inflammatory (auto)immune responses and can exhibit pro- or anti-inflammatory effects through (auto)antibody-dependent and -independent functions. Emerging evidence indicates a key role of nutrients and microbial metabolites in regulating the differentiation of plasma cells as well as their differentiation to pro- or anti-inflammatory phenotypes. These effects might be mediated indirectly by influencing other immune cells or directly through B cell-intrinsic mechanisms. Here, we provide an overview of nutrients and metabolites that influence B cell-intrinsic signaling pathways regulating B cell activation, plasma cell differentiation, and effector functions. Furthermore, we outline important inflammatory plasma cell phenotypes whose differentiation could be targeted by nutrients and microbial metabolites. Finally, we discuss possible implications for inflammatory (auto)immune conditions.

Keywords:  IL-10; IgG glycosylation; antibodies; autoimmunity; metabolism; metabolites; nutrients; plasma cells

DOI:  https://doi.org/10.3389/fimmu.2022.1004644
Cell Mol Immunol. 2022 Dec 05.

Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit.

Peng Xiao, Ziwei Hu, Jiaheng Lang, Tianyuan Pan, Randall Tyler Mertens, Huilun Zhang, Ke Guo, Manlu Shen, Hongqiang Cheng, Xue Zhang, Qian Cao, Yuehai Ke.

  Mannose is a naturally occurring sugar widely consumed in the daily diet; however, mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking. Herein, we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery. Macrophage-secreted inflammatory cytokines, particularly TNF-α, induced pathological endoplasmic reticulum stress (ERS) in intestinal epithelial cells (IECs), which was prevented by mannose via normalization of protein N-glycosylation. By preserving epithelial integrity, mannose reduced the inflammatory activation of colonic macrophages. On the other hand, mannose directly suppressed macrophage TNF-α production translationally by reducing the glyceraldehyde 3-phosphate level, thus promoting GAPDH binding to TNF-α mRNA. Additionally, we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease. Finally, we revealed that activating PMM2 activity with epalrestat, a clinically approved drug for the treatment of diabetic neuropathy, elicited further sensitization to the therapeutic effect of mannose. Therefore, mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages, thereby normalizing aberrant immunometabolism in the gut.

Keywords:  Colitis; Endoplasmic reticulum stress; Intestinal epithelial cells; Macrophages; Mannose; TNF-alpha

DOI:  https://doi.org/10.1038/s41423-022-00955-1
EBioMedicine. 2022 Nov 30. pii: S2352-3964(22)00564-3. [Epub ahead of print]86 104382

Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-responders.

Qing Xiao, Liting Yan, Junyan Han, Siyuan Yang, Yunxia Tang, Qun Li, Xiaojie Lao, Zhen Chen, Jiang Xiao, Hongxin Zhao, Fengting Yu, Fujie Zhang.

  BACKGROUND: HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood.METHODS: Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed.
FINDINGS: We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells.
INTERPRETATION: Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs.
FUNDING: This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126).

Keywords:  Ferroptosis; Human immunodeficiency virus (HIV); Immune non-responder (INR); Inflammation; Metabolism; Poor immune reconstitution (PIR)

DOI:  https://doi.org/10.1016/j.ebiom.2022.104382
Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00501-0. [Epub ahead of print]34(12): 1903-1905

Microbiome-derived metabolites counteract tumor-induced immunosuppression and boost immune checkpoint blockade.

Hassane M Zarour.

The tumor and gut microbiome regulate antitumor immunity and modulate responses to immune checkpoint blockade, although the mechanisms of action remain uncertain. A recent study in Science Immunology by Mirji et al. describes that the microbiota-generated metabolite trimethylamine N-oxide (TMAO) plays a critical role in mediating the effects of the microbiome on antitumor immunity.

DOI: https://doi.org/10.1016/j.cmet.2022.11.010
J Agric Food Chem. 2022 Dec 05.

Tetrahydroxy Stilbene Glucoside Alleviates Ischemic Stroke by Regulating Conformation-Dependent Intracellular Distribution of PKM2 for M2 Macrophage Polarization.

Minghui Li, Wei Lu, Yuanyuan Meng, Wenjie Zhang, Fengge Wang, Li Sun, Yuekang Xu.

  Tetrahydroxy stilbene glucoside (TSG) is a bioactive ingredient with powerful anti-inflammatory and neuroprotective properties. However, the detailed mechanisms concerning the neuroprotective effect of TSG are not fully understood. This study aims to address the molecular mechanism involved in the protective effects of TSG on murine ischemic stroke. We found that TSG meliorated the phenotypes of ischemic stroke in vivo, which was correlated with the increased percentage of infiltrated M2 macrophages in brain after stroke. Mechanistically, TSG regulated macrophage polarization by significantly downregulating the transcriptional levels of M1 marker genes (iNOS and IL-1β) but upregulating that of the M2 marker genes (arg-1 and IL-4) following lipopolysaccharide/interferon-γ stimulation. Consistently, TSG reversed the metabolic profiling of M1 macrophage toward the M2 status at intracellular energy levels. Surprisingly, the knockdown of an established metabolic enzyme pyruvate kinase M2 (PKM2) that is important for M1 switch in macrophages abolished the promotive effect of TSG on the M2 polarization. Further investigation revealed that TSG markedly downregulated the intracellular ratio of dimer/monomer to the tetramer of PKM2 without affecting its total protein expression, leading to a suppressed nuclear translocation of functioning PKM2 in macrophages for M1 differentiation. Taken together, we identified a novel mechanism for macrophage M2 polarization regulation by a small-molecule chemical that controls the quality (conformation) rather than the quantity (expression) of an intracellular M1-promoting metabolic enzyme, which offers a better understanding of the mechanisms of macrophage plasticity and has serious implication in translational strategies for the treatment of macrophage-mediated neurological diseases with natural bioactive products.

Keywords:  PKM2 conformation; ischemic stroke; macrophage polarization; tetrahydroxy stilbene glucoside

DOI:  https://doi.org/10.1021/acs.jafc.2c03923
Brain Behav Immun Health. 2022 Dec;26 100544

Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor.

Mieko Tokano, Sho Matsushita, Rie Takagi, Toshimasa Yamamoto, Masaaki Kawano.

  Extracellular adenosine, produced from ATP secreted by neuronal or immune cells, may play a role in endogenous regulation of inflammatory responses. Studies show that adenosine induces hypersecretion of IL-17A by CD4+ T cells upon treatment with an A2aR agonist (PSB0777), and that adenosine-mediated IL-17A hypersecretion is suppressed by the A2aR antagonist (Istradefylline) in humans. However, it is unclear whether A2aR downstream signaling is involved in IL-17A hypersecretion. Here, we show that inhibitors of adenyl cyclase (AC), protein kinase A (PKA), and cAMP response element binding protein (CREB) (which are signaling molecules downstream of the Gs protein coupled to the A2aR), suppress IL-17A production, suggesting that activation of A2aR signaling induces IL-17A production by CD4+ T cells. Furthermore, immune subset studies revealed that adenosine induces hypersecretion of IL-17A by T-helper (Th)17 cells. These results indicate that adenosine is an endogenous modulator of neutrophilic inflammation. Administration of an A2aR antagonist to mice with experimental autoimmune encephalomyelitis led to marked amelioration of symptoms. Thus, inhibitors of the novel A2aR-AC-cAMP-PKA-CREB signaling pathway for IL-17A hypersecretion by TCR-activated Th17 cells suppresses adenosine-mediated IL-17A production, suggesting that it may be an effective treatment for Th17-related autoimmune diseases.

Keywords:  Adenosine; Adenosine A2a receptor; CD4+ T cells; EAE; IL-17A; Th17 cells

DOI:  https://doi.org/10.1016/j.bbih.2022.100544
Nature. 2022 Dec 07.

Plant-cell machinery for making metabolites transferred to mammalian cells.



Keywords:  Biomaterials; Biotechnology; Metabolism; Regeneration

DOI:  https://doi.org/10.1038/d41586-022-03629-0
Nat Commun. 2022 Dec 06. 13(1): 7430

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.

Jawaher Alharthi, Ali Bayoumi, Khaled Thabet, Ziyan Pan, Brian S Gloss, Olivier Latchoumanin, Mischa Lundberg, Natalie A Twine, Duncan McLeod, Shafi Alenizi, Leon A Adams, Martin Weltman, Thomas Berg, Christopher Liddle, Jacob George, Mohammed Eslam.

The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.

DOI: https://doi.org/10.1038/s41467-022-35158-9