bims-imicid 2022-05-01 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–05–01
27 papers selected by
Dylan Ryan, University of Cambridge

Treatment with Exogenously Added Catalase Alters CD8 T Cell Memory Differentiation and Function.
Metabolism in tumor-associated macrophages.
Emerging role of the itaconate-mediated rescue of cellular metabolic stress.
The IRG1-Itaconate axis: A regulatory hub for immunity and metabolism in macrophages.
Lipid metabolism in T cell signaling and function.
Creating ATP via creatine kinase B for NLRP3 activation.
Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors.
The potential of using itaconate as treatment for inflammation-related heart diseases.
CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.
Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
Atossa: a royal link between OXPHOS metabolism and macrophage migration.
Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.
A protocol to assess cellular bioenergetics in flavivirus-infected cells.
Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.
Nur77 Deficiency Exacerbates Macrophage NLRP3 Inflammasome-Mediated Inflammation and Accelerates Atherosclerosis.
Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism.
Loss of hydrogen voltage-gated channel-1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T-cells.
Targeting Nuclear Receptors for TH17-Mediated Inflammation: REV-ERBerations of Circadian Rhythm and Metabolism.
Targeted autophagy disruption reveals the central role of macrophage iron metabolism in systemic iron homeostasis.
Amyloid-β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway.
Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.
Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2-Dependent Changes in Intracellular pH.
Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse.
Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.
Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion.
Metabolic adaptation to high starch diet in largemouth bass (Micropterus salmoides) was associated with the restoration of metabolic functions via inflammation, bile acid synthesis and energy metabolism.
Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.

Adv Biol (Weinh). 2022 Apr 28. e2101320

Treatment with Exogenously Added Catalase Alters CD8 T Cell Memory Differentiation and Function.

Halil-Ibrahim Aksoylar, Nikolaos Patsoukis.

  Cell-based immunotherapy is a promising approach to cancer treatment. However, the metabolically hostile tumor microenvironment (TME) poses a major barrier to this therapeutic approach. Metabolic reprogramming may enhance T cell effector function and support longevity and persistence within the TME. Metabolic processes lead reactive oxygen species (ROS) production, which are mandatory mediators of signaling and immune cell functions, but detrimental when present in excess. Catalase (CAT) is an intracellular antioxidant enzyme that scavenges hydrogen peroxide (H2 O2 ), a central ROS member with a plethora of biological effects. H2 O2 is produced intracellularly and extracellularly, diffusing freely between the two compartments. In this study, it is found that scavenging extracellular H2 O2 by CAT supplementation has a major impact on the cell redox state, decreased intracellular ROS, but enhanced activation and altered memory differentiation. Under in vitro chronic activation conditions, CAT treatment favors CD8 T cells with less exhausted phenotype, increased activation and memory markers, and high bioenergetic capacity. Under in vitro acute activation conditions, CAT treatment selectively prevents differentiation transition from the stem cell memory/naive (TSCM /TN )- to the central memory (TCM )-like phenotype, while enhancing activation and polyfunctionality. The study highlights the critical role of H2 O2 as a "hidden player" in T cell fitness and memory differentiation.

Keywords:  T cell differentiation; effector; exhaustion; hydrogen peroxide; memory; metabolism; reactive oxygen species

DOI:  https://doi.org/10.1002/adbi.202101320
Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00004-1. [Epub ahead of print]367 65-100

Metabolism in tumor-associated macrophages.

Jie Li, Gina M DeNicola, Brian Ruffell.

  Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.

Keywords:  Immunometabolism; Metabolic reprogramming; Metabolism; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/bs.ircmb.2022.01.004
Tzu Chi Med J. 2022 Apr-Jun;34(2):34(2): 134-138

Emerging role of the itaconate-mediated rescue of cellular metabolic stress.

Der-Shan Sun, Hsin-Hou Chang.

  Metabolic regulations play vital roles on maintaining the homeostasis of our body. Evidence have suggested that ATF3 and nuclear factor erythroid 2-related factor 2 (NRF2) are critical for maintaining cell function, metabolism, and inflammation/anti-inflammation regulations when cells are under stress, while the upstream regulators in the stressed cells remain elusive. Recent findings have shown that tricarboxylic acid cycle metabolites such as itaconate and succinate are not just mitochondrial metabolites, but rather important signaling mediators, involving in the regulations of metabolism, immune modulation. Itaconate exerts anti-inflammatory role through regulating ATF3 and NRF2 pathways under stressed conditions. In addition, itaconate inhibits succinate dehydrogenase, succinate oxidation and thus blocking succinate-mediated inflammatory processes. These findings suggest itaconate-ATF3 and itaconate-NRF2 axes are well-coordinated machineries that facilitate the rescue against cellular stress. Here, we review these fascinating discoveries, a research field may help the development of more effective therapeutic approach to manage stress-induced inflammation, tissue damage, and metabolic disorder.

Keywords:  ATF3; Inflammasome; Itaconate; Mitochondrial stress; Nuclear factor erythroid 2–related factor 2

DOI:  https://doi.org/10.4103/tcmj.tcmj_79_21
Int Rev Immunol. 2022 Apr 25. 1-15

The IRG1-Itaconate axis: A regulatory hub for immunity and metabolism in macrophages.

Yangguang Li, Wenbin Gong, Weizhen Li, Peizhao Liu, Juanhan Liu, Haiyang Jiang, Tao Zheng, Jie Wu, Xiuwen Wu, Yun Zhao, Jianan Ren.

  Metabolism could be served as a guiding force for immunity, and macrophages undergo drastic metabolic reprogramming during inflammatory processes, including enhancing glycolysis and reshaping the tricarboxylic acid cycle (TCA) cycle. The disrupted TCA cycle facilitates itaconate accumulation, consistent with the significant up-regulation of immune response gene 1 (IRG1) in activated macrophages. IRG1 catalyzes the decarboxylation of cis-aconitate to synthesize itaconate, and notably, the IRG1-Itaconate axis has excellent potential to link macrophages' immunity and metabolism. Here, we review vital molecules that affect the activation of the IRG1-Itaconate axis, including interferon regulatory factor 1/9 (IRF1/9), transcription 1 and 3 (STAT1/3), CCAAT enhancer-binding protein β (C/EBPβ), and the protein kinase C (PKC). We then focus on how the IRG1-Itaconate axis regulates the inflammatory pathway in macrophages, proposed to involve kelch-like ECH-associated protein 1 (Keap1), NOD-, LRR- and pyrin domain-containing 3 (NLRP3), gasdermin D (GSDMD), activating transcription factor 3 (ATF3), receptor-interacting protein kinase-3 (RIPK3), et al. In addition, we provide an overview of the way the axis participates in the metabolism of macrophages. Eventually, we summarize current connections between the IRG1-Itaconate axis and inflammatory diseases, bringing light to new therapeutic opportunities in inflammatory diseases.

Keywords:  IRG1; immunity; itaconate; macrophage; metabolism

DOI:  https://doi.org/10.1080/08830185.2022.2067153
Nat Chem Biol. 2022 May;18(5): 470-481

Lipid metabolism in T cell signaling and function.

Seon Ah Lim, Wei Su, Nicole M Chapman, Hongbo Chi.

T cells orchestrate adaptive immunity against pathogens and other immune challenges, but their dysfunction can also mediate the pathogenesis of cancer and autoimmunity. Metabolic adaptation in response to immunological and microenvironmental signals contributes to T cell function and fate decision. Lipid metabolism has emerged as a key regulator of T cell responses, with selective lipid metabolites serving as metabolic rheostats to integrate environmental cues and interplay with intracellular signaling processes. Here, we discuss how extracellular, de novo synthesized and membrane lipids orchestrate T cell biology. We also describe the roles of lipids as regulators of intracellular signaling at the levels of transcriptional, epigenetic and post-translational regulation in T cells. Finally, we summarize therapeutic targeting of lipid metabolism and signaling, and conclude with a discussion of important future directions. Understanding the molecular and functional interplay between lipid metabolism and T cell biology will ultimately inform therapeutic intervention for human disease.

DOI: https://doi.org/10.1038/s41589-022-01017-3
Nat Immunol. 2022 Apr 28.

Creating ATP via creatine kinase B for NLRP3 activation.

Juliana E Toller-Kawahisa, Luke A J O'Neill.

DOI: https://doi.org/10.1038/s41590-022-01191-5
Viral Immunol. 2022 Apr;35(3): 223-235

Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors.

Lucas T Jennelle, Tshifhiwa Magoro, Angelina R Angelucci, Aditya Dandekar, Young S Hahn.

  Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the development of steatohepatitis and fibrogenesis. Chronic HCV patients have increased liver macrophages with disruptions in cholesterol metabolism and alterations in inflammatory mediators. While HCV-induced changes in inflammatory mediators are well documented, how HCV triggers metabolic change in macrophages is unknown. In this report, we examined the mechanism of macrophage sensing of HCV to cause metabolic impairment and subsequent immune dysfunction. We demonstrate that HCV protein and RNA kinetics in macrophages are distinct from hepatocytes. In macrophages, HCV RNAs and protein accumulate rapidly after exposure but internalized RNAs quickly decline to a low-level set point. Notably, exposure of macrophages to HCV resulted in increased lipids and cholesterol and activation of cholesterol-sensing, immunomodulatory liver X receptors (LXRs). Furthermore, we provide evidence that HCV RNA accumulation in macrophages occurs through scavenging receptors. These results suggest that HCV released from infected hepatocytes stimulates accumulation of lipids and activation of LXR in macrophages contributing to metabolic changes involved in HCV-induced chronic liver disease. Our results provide novel insight into mechanisms through which impaired lipid metabolism in macrophages associated with HCV infection promotes development of liver steatohepatitis and fibrosis.

Keywords:  LXR; SR-B1; cholesterol; hepatitis C virus; macrophages; scavenger receptor

DOI:  https://doi.org/10.1089/vim.2021.0101
Tzu Chi Med J. 2022 Apr-Jun;34(2):34(2): 113-118

The potential of using itaconate as treatment for inflammation-related heart diseases.

Hui-Chen Ku, Ta-Chung Shen, Ching-Feng Cheng.

  Intracellular metabolites can cause critical changes in biological functions. Itaconate is perhaps the most fascinating substance in macrophages. Lipopolysaccharide can activate aconitate decarboxylase 1 and induces the generation of itaconate from the tricarboxylic acid cycle by decarboxylation of cis-aconitate. It has been reported that itaconate has beneficial effects on inflammation and oxidation. The mechanisms involved in these effects include the suppression of succinate dehydrogenase, the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, suppression of aerobic glycolysis through regulation of glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, and suppression of IκBζ translation through activating transcription factor 3 activation. All of these findings elucidated the possible therapeutic implications of itaconate in inflammation-related diseases. In this review, we highlight that itaconate is a crucial molecule of the immunomodulatory response in macrophages and can regulate between immune response and cardiovascular metabolism. Furthermore, these discoveries suggest that itaconate is a very novel therapeutic molecule for the treatment of inflammation-related heart diseases.

Keywords:  Activating transcription factor 3; Inflammation; Itaconate; Nuclear factor erythroid 2-related factor 2; Succinate dehydrogenase

DOI:  https://doi.org/10.4103/tcmj.tcmj_83_21
Immunometabolism. 2022 ;pii: e220008. [Epub ahead of print]4(2):

CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.

Maria Maryanovich, Keisuke Ito.

  Hematopoietic homeostasis depends on the close regulation of hematopoietic stem cell (HSC) activity in the bone marrow. Quiescence and activation in response to stress, among other changes in state, are mediated by shifts in HSC metabolic activity. Although HSC steady-state metabolism is well established, the mechanisms driving HSC activation, proliferation, and differentiation in response to stress remain poorly understood. Here we discuss a study by Mistry et al. that describes a novel metabolic mechanism that fuels HSC activation and expansion. The authors show that to meet their metabolic needs in response to infection, hematopoietic stem and progenitor cells uptake free fatty acids from their microenvironment via CD36 to fuel fatty acid oxidation. These exciting findings suggest that in the context of infection, HSCs undergo a metabolic shift toward fatty acid metabolism that drives emergency hematopoiesis and raise questions about the role of the microenvironment in this process.

Keywords:  CD36; fatty-acid oxidation; hematopoiesis; hematopoietic stem cells; infection; oxidative phosphorylation

DOI:  https://doi.org/10.20900/immunometab20220008
Nat Immunol. 2022 Apr 28.

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.

Leah K Billingham, Joshua S Stoolman, Karthik Vasan, Arianne E Rodriguez, Taylor A Poor, Marten Szibor, Howard T Jacobs, Colleen R Reczek, Aida Rashidi, Peng Zhang, Jason Miska, Navdeep S Chandel.

The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.

DOI: https://doi.org/10.1038/s41590-022-01185-3
EMBO J. 2022 Apr 25. e111290

Atossa: a royal link between OXPHOS metabolism and macrophage migration.

Pedro Latorre-Muro, Pere Puigserver.

The ability of immune cells to penetrate affected tissues is highly dependent on energy provided by mitochondria, yet their involvement in promoting migration remains unclear. Recent work by Emtenani et al (2022) describes a nuclear Atossa-Porthos axis that adjusts transcription and translation of a small subset of OXPHOS genes to increase mitochondrial bioenergetics and allow macrophage tissue invasion in flies.

DOI: https://doi.org/10.15252/embj.2022111290
Nat Metab. 2022 Apr;4(4): 476-494

Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.

V Pellegrinelli, S Rodriguez-Cuenca, C Rouault, E Figueroa-Juarez, H Schilbert, S Virtue, J M Moreno-Navarrete, G Bidault, M C Vázquez-Borrego, A R Dias, B Pucker, M Dale, M Campbell, S Carobbio, Y H Lin, M Vacca, J Aron-Wisnewsky, S Mora, M M Masiero, A Emmanouilidou, S Mukhopadhyay, G Dougan, M den Hoed, R J F Loos, J M Fernández-Real, D Chiarugi, K Clément, A Vidal-Puig.

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.

DOI: https://doi.org/10.1038/s42255-022-00561-5
STAR Protoc. 2022 Jun 17. 3(2): 101297

A protocol to assess cellular bioenergetics in flavivirus-infected cells.

John Z H Low, Clement Yau, Summer L X Zhang, Hwee Cheng Tan, Eng Eong Ooi, Kuan Rong Chan.

  Aberrant cellular bioenergetics has detrimental consequences in host cells. For instance, pathogenic Zika virus strains can suppress mitochondria respiration and glycolytic functions, disrupting cellular bioenergetics that leads to apoptosis. Herein, we describe methods for flavivirus propagation, titering and infection, cell preparation, and procedures for mitochondrial and glycolytic stress tests. The protocol enables assessment of cellular respiration and glycolytic flux in flavivirus-infected cells. For complete details on the use and execution of this protocol, please refer to Yau et al. (2021).

Keywords:  Cell Biology; Cell culture; Cell-based Assays; Metabolism; Microbiology; Molecular Biology

DOI:  https://doi.org/10.1016/j.xpro.2022.101297
Nat Cancer. 2022 Apr;3(4): 384-385

Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.

DOI: https://doi.org/10.1038/s43018-022-00350-9
Oxid Med Cell Longev. 2022 ;2022 2017815

Nur77 Deficiency Exacerbates Macrophage NLRP3 Inflammasome-Mediated Inflammation and Accelerates Atherosclerosis.

Ruosen Yuan, Weifeng Zhang, Peng Nie, Keke Lan, Xiaoxiao Yang, Anwen Yin, Qingqing Xiao, Yejiao Shen, Ke Xu, Xia Wang, Xin Pan, Linghong Shen, Ben He.

Purpose: Activation of NLR (nucleotide-binding and leucine-rich repeat immune receptor) family pyrin domain containing 3 (NLRP3) inflammasome mediating interleukin- (IL-) 1β secretion has emerged as an important component of inflammatory processes in atherogenesis. The nuclear receptor Nur77 is highly expressed in human atherosclerotic lesions; however, its functional role in macrophage NLRP3 inflammasome activation has not yet been clarified. Methods, Materials, and Results. Eight-week-old apolipoprotein E (ApoE)-/- and ApoE-/- Nur77-/- mice that were fed a Western diet underwent partial ligation of the left common carotid artery (LCCA) and left renal artery (LRA) to induce atherogenesis. Four weeks later, severe plaque burden associated with increased lipid deposition, reduced smooth muscle cells, macrophage infiltration, and decreased collagen expression was identified in ApoE-/- Nur77-/- mice compared with those in ApoE-/- mice. ApoE-/- Nur77-/- mice showed increased macrophage inflammatory responses in carotid atherosclerotic lesions. In vitro studies demonstrated that oxidized low-density lipoprotein cholesterol (ox-LDL) increased the release of lactate dehydrogenase (LDH) and upregulated the expressions of cleaved caspase-1, cleaved IL-1β and gasdermin D (GSMD) in WT peritoneal macrophages (PMs) in a NLRP3-dependent manner. Nur77-/- PMs exhibited a further increased level of NLRP3 inflammasome-mediated inflammation under ox-LDL treatment compared with WT PMs. Mechanistically, Nur77 could bind to the promoter of NLRP3 and inhibit its transcriptional activity.
Conclusions: This study demonstrated that Nur77 deletion promotes atherogenesis by exacerbating NLRP3 inflammasome-mediated inflammation.

DOI: https://doi.org/10.1155/2022/2017815
Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2112781119

Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism.

Polly Downton, Fabio Sanna, Robert Maidstone, Toryn M Poolman, Edward A Hayter, Suzanna H Dickson, Nick A Ciccone, James O Early, Antony Adamson, David G Spiller, Devin A Simpkins, Matthew Baxter, Roman Fischer, Magnus Rattray, Andrew S I Loudon, Julie E Gibbs, David A Bechtold, David W Ray.

  SignificanceRheumatoid arthritis (RA) is a debilitating chronic inflammatory disease in which symptoms exhibit a strong time-of-day rhythmicity. RA is commonly associated with metabolic disturbance and increased incidence of diabetes and cardiovascular disease, yet the mechanisms underlying this metabolic dysregulation remain unclear. Here, we demonstrate that rhythmic inflammation drives reorganization of metabolic programs in distal liver and muscle tissues. Chronic inflammation leads to mitochondrial dysfunction and dysregulation of fatty acid metabolism, including accumulation of inflammation-associated ceramide species in a time-of-day-dependent manner. These findings reveal multiple points for therapeutic intervention centered on the circadian clock, metabolic dysregulation, and inflammatory signaling.

Keywords:  ceramide; circadian clock; inflammation; mitochondria; rheumatoid arthritis

DOI:  https://doi.org/10.1073/pnas.2112781119
JCI Insight. 2022 Apr 26. pii: e147814. [Epub ahead of print]

Loss of hydrogen voltage-gated channel-1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T-cells.

David Coe, Thanushiyan Poobalasingam, Hongmei Fu, Fabrizia Bonacina, Guosu Wang, Valle Morales, Annalisa Moregola, Nico Mitro, Kenneth Cp Cheung, Eleanor J Ward, Suchita Nadkarni, Dunja Aksentijevic, Katiuscia Bianchi, Giuseppe Danilo Norata, Melania Capasso, Federica M Marelli-Berg.

  Hvcn1 is a voltage-gated proton channel, which reduces cytosol acidification and facilitates the production of reactive oxygen species (ROS). The increased expression of this channel in some cancers, has led to proposing Hvcn1 antagonists as potential therapeutics.While its role in most leukocytes has been studied in-depth, the function of Hvcn1 in T-cells remains poorly defined. We show that HVCN1 plays a non-redundant role in protecting naïve T-cells from intracellular acidification during priming. Despite sharing overall functional impairment in vivo and in vitro, Hvcn1-deficient CD4+ and CD8+ T-cells display profound differences during the transition from naïve to primed T-cells, including in the preservation of TCR signaling, cellular division and death. These selective features result, at least in part, from a substantially different metabolic response to intracellular acidification associated with priming. While Hvcn1-deficient naïve CD4+ T-cells reprogram to rescue the glycolytic pathway, naïve CD8+ T-cells, which express high levels of this channel in the mitochondria, respond by metabolically compensating mitochondrial dysfunction, at least in part via AMPK activation.These observations imply heterogeneity between adaptation of naïve CD4+ and CD8+ T-cells to intracellular acidification during activation.

Keywords:  Adaptive immunity; Immunology

DOI:  https://doi.org/10.1172/jci.insight.147814
Immunometabolism. 2022 Apr 18. pii: e220006. [Epub ahead of print]4(2):

Targeting Nuclear Receptors for TH17-Mediated Inflammation: REV-ERBerations of Circadian Rhythm and Metabolism.

Sarah A Mosure, Adrianna N Wilson, Laura A Solt.

  Since their discovery, a significant amount of progress has been made understanding T helper 17 (TH17) cells' roles in immune homeostasis and disease. Outside of classical cytokine signaling, environmental and cellular intrinsic factors, including metabolism, have proven to be critical for non-pathogenic vs pathogenic TH17 cell development, clearance of infections, and disease. The nuclear receptor RORγt has been identified as a key regulator of TH17-mediated inflammation. Nuclear receptors regulate a variety of physiological processes, ranging from reproduction to the circadian rhythm, immunity to metabolism. Outside of RORγt, the roles of other nuclear receptors in TH17-mediated immunity are not as well established. In this mini-review we describe recent studies that revealed a role for a different member of the nuclear receptor superfamily, REV-ERBα, in the regulation of TH17 cells and autoimmunity. We highlight similarities and differences between reports, potential roles beyond TH17-mediated cytokine regulation, unresolved questions in the field, as well as the translational potential of targeting REV-ERBα.

Keywords:  REV-ERB; RORγt; T regulatory; TH17 cell; inflammation; metabolism; nuclear receptor

DOI:  https://doi.org/10.20900/immunometab20220006
Blood. 2022 Apr 26. pii: blood.2021014493. [Epub ahead of print]

Targeted autophagy disruption reveals the central role of macrophage iron metabolism in systemic iron homeostasis.

Meriem Taleb, Isabelle Maillet, Marc Le Bert, Catherine Mura.

Iron homeostasis depends on both intracellular control through iron-responsive proteins and the systemic level of iron through hepcidin-ferroportin axis. Indeed, the hormone hepcidin downregulates the ferroportin iron exporter to control iron recycling from macrophages and iron uptake from enterocytes. Here, we focused on the role of autophagy in macrophage iron metabolism and systemic iron homeostasis. Mice deficient for autophagy in macrophages (LysM-Atg5-/-) mimicked a primary iron overload phenotype, resulting in high ferroportin expression in both macrophages and enterocytes that correlated with marked parenchymal iron overload. Furthermore, LysM-Atg5-/- mice exhibited increased hematopoietic activity with no sign of anemia but correlating with rather high plasma iron level. Compared to wild-type cells, bone marrow-derived macrophages from LysM-Atg5-/- mice had significantly increased ferroportin expression and a decreased iron content, confirming high iron export. In erythrophagocytic macrophages autophagy regulates hemosiderin storage mechanisms as well as the degradation of ferroportin and subsequently its plasma membrane localization and iron export; further, ferroportin colocalization with hepcidin indicates hepcidin autocrine activity. Relatively high hepatic hepcidin expression, and decreased hepcidin level in the spleen of LysM-Atg5-/- mice correlating with low hemosiderin iron storage as well as in erythrophagocytic Atg5-/- macrophages were evidenced. Therefore, our results highligh the critical role of autophagy in macrophages for iron trafficking and systemic iron homeostasis. We propose that in macrophages, autophagy restricts ferroportin level and iron export resulting in hepcidin expression with an autocrine-paracrine effect that takes part in the regulation of the ferroportin expression in duodenal enterocytes.

DOI: https://doi.org/10.1182/blood.2021014493
Aging Cell. 2022 Apr 27. e13623

Amyloid-β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway.

Eun Sun Jung, Kyujin Suh, Jihui Han, Heyyoung Kim, Hyung-Sik Kang, Won-Seok Choi, Inhee Mook-Jung.

  Neuroinflammation is considered one of major factors in the pathogenesis of Alzheimer's disease (AD). In particular, inflammasome activation, including NLRP3 inflammasome in microglia, is regarded as fundamental for the pro-inflammatory response of immune cells. However, the precise molecular mechanism through which the NLRP3 inflammasome is associated with AD pathologies remains unclear. Here, we show that amyloid-β activates the NLRP3 inflammasome in microglia by activating Syk and inhibiting AMPK. Deactivated AMPK induces metabolic dysregulation, mitochondrial fragmentation, and reactive oxygen species formation, leading to the activation of the NLRP3 inflammasome. In addition, flufenamic acid (FA), a member of non-steroidal anti-inflammatory drugs, was found to effectively inhibit activation of the microglial NLRP3 inflammasome by regulating Syk and AMPK. Importantly, FA has marked therapeutic effects on major AD pathologies and memory function in vivo in microglia-dependent way. All together, these findings demonstrate the molecular mechanism of microglial NLRP3 inflammasome activation by amyloid-β, which acts as an important mediator of neuroinflammation. Also, we suggest that repurposing of FA for inhibiting microglial activation of the NLRP3 inflammasome is a potential treatment for AD.

Keywords:  Alzheimer's disease; inflammasome; microglia

DOI:  https://doi.org/10.1111/acel.13623
Sci Immunol. 2022 Apr 29. 7(70): eabm8161

Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.

Xuyong Chen, Benjamin Sunkel, Meng Wang, Siwen Kang, Tingting Wang, J N Rashida Gnanaprakasam, Lingling Liu, Teresa A Cassel, David A Scott, Ana M Muñoz-Cabello, Jose Lopez-Barneo, Jun Yang, Andrew N Lane, Gang Xin, Benjamin Z Stanton, Teresa W-M Fan, Ruoning Wang.

Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.

DOI: https://doi.org/10.1126/sciimmunol.abm8161
J Immunol. 2022 Apr 27. pii: ji2100665. [Epub ahead of print]

Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2-Dependent Changes in Intracellular pH.

Moritz J Strowitzki, Ross Nelson, Mario P Garcia, Christopher Tuffs, Marc B Bleul, Stephen Fitzsimons, Javier Navas, Ilona Uzieliene, Alina S Ritter, David Phelan, Sarah J Kierans, Alfonso Blanco, Eiva Bernotiene, Orina Belton, Martin Schneider, Eoin P Cummins, Cormac T Taylor.

CO2, the primary gaseous product of respiration, is a major physiologic gas, the biology of which is poorly understood. Elevated CO2 is a feature of the microenvironment in multiple inflammatory diseases that suppresses immune cell activity. However, little is known about the CO2-sensing mechanisms and downstream pathways involved. We found that elevated CO2 correlates with reduced monocyte and macrophage migration in patients undergoing gastrointestinal surgery and that elevated CO2 reduces migration in vitro. Mechanistically, CO2 reduces autocrine inflammatory gene expression, thereby inhibiting macrophage activation in a manner dependent on decreased intracellular pH. Pharmacologic or genetic inhibition of carbonic anhydrases (CAs) uncouples a CO2-elicited intracellular pH response and attenuates CO2 sensitivity in immune cells. Conversely, CRISPR-driven upregulation of the isoenzyme CA2 confers CO2 sensitivity in nonimmune cells. Of interest, we found that patients with chronic lung diseases associated with elevated systemic CO2 (hypercapnia) display a greater risk of developing anastomotic leakage following gastrointestinal surgery, indicating impaired wound healing. Furthermore, low intraoperative pH levels in these patients correlate with reduced intestinal macrophage infiltration. In conclusion, CO2 is an immunomodulatory gas sensed by immune cells through a CA2-coupled change in intracellular pH.

DOI: https://doi.org/10.4049/jimmunol.2100665
Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00511-3. [Epub ahead of print]39(4): 110747

Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse.

Gaurang Jhala, Balasubramanian Krishnamurthy, Thomas C Brodnicki, Tingting Ge, Satoru Akazawa, Claudia Selck, Prerak M Trivedi, Evan G Pappas, Leanne Mackin, Nicola Principe, Erwan Brémaud, David J De George, Louis Boon, Ian Smyth, Jonathan Chee, Thomas W H Kay, Helen E Thomas.

  Interferon gamma (IFNγ) is a proinflammatory cytokine implicated in autoimmune diseases. However, deficiency or neutralization of IFNγ is ineffective in reducing disease. We characterize islet antigen-specific T cells in non-obese diabetic (NOD) mice lacking all three IFN receptor genes. Diabetes is minimally affected, but at 125 days of age, antigen-specific CD8+ T cells, quantified using major histocompatibility complex class I tetramers, are present in 10-fold greater numbers in Ifngr-mutant NOD mice. T cells from Ifngr-mutant mice have increased proliferative responses to interleukin-2 (IL-2). They also have reduced phosphorylated STAT1 and its target gene, suppressor of cytokine signaling 1 (SOCS-1). IFNγ controls the expansion of antigen-specific CD8+ T cells by mechanisms which include increased SOCS-1 expression that regulates IL-2 signaling. The expanded CD8+ T cells are likely to contribute to normal diabetes progression despite reduced inflammation in Ifngr-mutant mice.

Keywords:  CP: Immunology; MHC tetramers; autoimmune diabetes; interferons; interleukin-2; suppressor of cytokine singling 1

DOI:  https://doi.org/10.1016/j.celrep.2022.110747
Immunity. 2022 Apr 20. pii: S1074-7613(22)00172-8. [Epub ahead of print]

Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.

Karen Agaronyan, Lokesh Sharma, Bharat Vaidyanathan, Keith Glenn, Shuang Yu, Charles Annicelli, Talia D Wiggen, Mitchell R Penningroth, Ryan C Hunter, Charles S Dela Cruz, Ruslan Medzhitov.

  Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response-a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This "niche remodeling" by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.

Keywords:  LasB; P. aeruginosa; allergic inflammation; amphiregulin; immune deviation; lung; mucin; opportunistic pathogen; type 2 immunity

DOI:  https://doi.org/10.1016/j.immuni.2022.04.001
mBio. 2022 Apr 25. e0067622

Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion.

Stephan Brouwer, Magnus G Jespersen, Cheryl-Lynn Y Ong, David M P De Oliveira, Bernhard Keller, Amanda J Cork, Karrera Y Djoko, Mark R Davies, Mark J Walker.

  The nasopharynx and the skin are the major oxygen-rich anatomical sites for colonization by the human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]). To establish infection, GAS must survive oxidative stress generated during aerobic metabolism and the release of reactive oxygen species (ROS) by host innate immune cells. Glutathione is the major host antioxidant molecule, while GAS is glutathione auxotrophic. Here, we report the molecular characterization of the ABC transporter substrate binding protein GshT in the GAS glutathione salvage pathway. We demonstrate that glutathione uptake is critical for aerobic growth of GAS and that impaired import of glutathione induces oxidative stress that triggers enhanced production of the reducing equivalent NADPH. Our results highlight the interrelationship between glutathione assimilation, carbohydrate metabolism, virulence factor production, and innate immune evasion. Together, these findings suggest an adaptive strategy employed by extracellular bacterial pathogens to exploit host glutathione stores for their own benefit. IMPORTANCE During infection, microbes must escape host immune responses and survive exposure to reactive oxygen species produced by immune cells. Here, we identify the ABC transporter substrate binding protein GshT as a key component of the glutathione salvage pathway in glutathione-auxotrophic GAS. Host-acquired glutathione is crucial to the GAS antioxidant defense system, facilitating escape from the host innate immune response. This study demonstrates a direct link between glutathione assimilation, aerobic metabolism, and virulence factor production in an important human pathogen. Our findings provide mechanistic insight into host adaptation that enables extracellular bacterial pathogens such as GAS to exploit the abundance of glutathione in the host cytosol for their own benefit.

Keywords:  Streptococcus pyogenes; glutathione uptake; immune evasion; oxidative stress; redox homeostasis; virulence regulation

DOI:  https://doi.org/10.1128/mbio.00676-22
Br J Nutr. 2022 Apr 27. 1-38

Metabolic adaptation to high starch diet in largemouth bass (Micropterus salmoides) was associated with the restoration of metabolic functions via inflammation, bile acid synthesis and energy metabolism.

P Chen, Y P Zhu, X F Wu, X Gu, M Xue, X F Liang.

  A short-term 2-week (2w) and long-term 8-week (8w) feeding trial was conducted to investigate the effects of low and high starch diets on the growth performance, metabolism and liver health of largemouth bass (Micropterus salmoides). Two isonitrogenous and isolipidic diets containing two levels of starch (LS, 9.06%; HS, 13.56%) were fed to largemouth bass. The results indicated that HS diet had no significant effects on SGR during 2w, whereas significantly lowered SGR at 8w. HS diet significantly increased hepatic glycolysis and gluconeogenesis at postprandial 24h in 2w. The HSI, plasma AKP, TBA levels, and hepatic glycogen, TG, TC, TBA, NEFA contents were significantly increased in the HS group at 2w. Moreover, HS diet up-regulated fatty acid and TG synthesis-related genes, and down-regulated of TG hydrolysis and β oxidation-related genes. Therefore, the glucolipid metabolism disorders resulted in metabolic liver disease induced by HS diet at 2w. However, the up-regulation of bile acid synthesis, inflammation and energy metabolism-related genes in 2w indicated that largemouth bass was still in a state of "self-repair" response. Interestingly, all the metabolic parameters were returned to homeostasis, with up-regulation of intestinal glucose uptake and transport-related genes, even hepatic histopathological analysis showed no obvious abnormality in the HS group in 8w. In conclusion, HS feed induced short-term acute metabolic disorder, but long-term metabolic adaptation to HS diet was related to repairing metabolism disorders via improving inflammatory responses, bile acid synthesis, and energy metabolism. These results strongly indicated that the largemouth bass owned certain adaptability to high starch diet.

Keywords:  Largemouth bass; glucose metabolism; high starch; lipid metabolism; metabolic liver disease

DOI:  https://doi.org/10.1017/S0007114522001180
PLoS Pathog. 2022 Apr 29. 18(4): e1010503

Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.

Guillaume N Fiches, Zhenyu Wu, Dawei Zhou, Ayan Biswas, Tai-Wei Li, Weili Kong, Maxime Jean, Netty G Santoso, Jian Zhu.

Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi's sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies.

DOI: https://doi.org/10.1371/journal.ppat.1010503