bims-imicid 2024-10-06 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–10–06
23 papers selected by
Dylan Ryan, University of Cambridge

Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.
Transcriptional Regulation and Function of Malic Enzyme 1 in Human Macrophage Activation.
Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6Chigh monocyte recruitment.
Intracellular Methylglyoxal Accumulation in Classically Activated Mouse Macrophages is Mediated by HIF-1α.
Selenoprotein o as a regulator of macrophage metabolism in selenium deficiency-induced lung inflammation.
Fuelling B cells: dynamic regulation of B cell metabolism.
Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.
Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.
TLR2 reprograms glucose metabolism in CD4+ T cells of rheumatoid arthritis patients to mediate cell hyperactivation and TNF-α secretion.
Metabolic Dependency Shapes Bivalent Antiviral Response in Host Cells in Response to Poly:IC: The Role of Glutamine.
MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.
Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials.
Immunometabolic Chaos in Septic Shock.
The role and therapeutic potential of itaconate in lung disease.
Anti-inflammatory effects of 1,7-dihydroxy-3,4-dimethoxyxanthone through inhibition of M1-phenotype macrophages via arginine/mitochondrial axis.
Immunometabolic Mechanisms of LANCL2 in CD4+ T Cells and Phagocytes Provide Protection from Systemic Lupus Erythematosus.
Myeloid PGC1β attenuates high-fat-diet induced inflammation via mitochondrial fission/mtDNA/Nlrp3 pathway.
Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion.
Aconitate decarboxylase 1 mediates the acute airway inflammatory response to environmental exposures.
Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance.
Immunometabolic regulation of germinal centers and its implications for aging.
Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.

J Leukoc Biol. 2024 Oct 01. pii: qiae198. [Epub ahead of print]

Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.

Margaret A McBride, Katherine R Caja, Tazeen K Patil, Allison M Owen, Liming Luan, Julia K Bohannon, Antonio Hernandez, Cody L Stothers, Irina A Trenary, Mohsin Rahim, Jamey D Young, M Wade Calcutt, Victoria R Stephens, Xenia Davis, Mary A Oliver, Dan Hao, Clara Si, Malik McRae, Kenny K Nguyen, Nicholas S Davis, Jingbin Wang, Naeem K Patil, Edward R Sherwood.

  Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) cycle reprogramming to innate immune memory. We observed that priming of wild type (WT) mice with MPLA potently facilitated accumulation of the TCA cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in immuneresponsive gene 1 (Irg1) -deficient mice. We further observed that MPLA potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to WT macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. MPLA-induced augmentation of glycolysis, oxidative phosphorylation and accumulation of the TCA cycle metabolites succinate and malate was decreased in Irg1 KO macrophages compared to WT controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1 deficient macrophages. This study identifies a contribution of itaconate to MPLA-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.

Keywords:  Immune Responsive Gene; Innate Immune Memory; Itaconate; Macrophages; Monophosphoryl Lipid A

DOI:  https://doi.org/10.1093/jleuko/qiae198
Biomedicines. 2024 Sep 13. pii: 2089. [Epub ahead of print]12(9):

Transcriptional Regulation and Function of Malic Enzyme 1 in Human Macrophage Activation.

Anna Santarsiero, Simona Todisco, Paolo Convertini, Chiara De Leonibus, Vittoria Infantino.

  Macrophages represent primary players of the innate immune system. Macrophage activation triggers several signaling pathways and is tightly associated with metabolic changes, which drive different immune subsets. Recent studies unveil the role of various metabolic enzymes in macrophage activation. Here, we show that malic enzyme 1 (ME1) is overexpressed in LPS-induced macrophages. Through chromatin immunoprecipitation, we demonstrate that ME1 transcriptional regulation is under control of NF-κB. Furthermore, ME1 activity is also increased in activated human PBMC-derived macrophages. Notably, ME1 gene silencing decreases nitric oxide as well as reactive oxygen species and prostaglandin E2 inflammatory mediators. Therefore, modulating ME1 provides a potential approach for immunometabolic regulation and in turn macrophage function.

Keywords:  NF-κB; PGE2; gene expression; immunometabolism; inflammation; macrophage activation; malic enzyme 1; nitric oxide; reactive oxygen species

DOI:  https://doi.org/10.3390/biomedicines12092089
Biol Direct. 2024 Sep 30. 19(1): 86

Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6Chigh monocyte recruitment.

Song Shen, Jianhui Li, Zhonghai Wei, Yihai Liu, Lina Kang, Rong Gu, Xuan Sun, Biao Xu, QiaoLing Li.

  The immune response gene 1 (IRG1) and its metabolite itaconate are implicated in modulating inflammation and oxidative stress, with potential relevance to sepsis-induced myocardial dysfunction (SIMD). This study investigates their roles in SIMD using both in vivo and in vitro models. Mice were subjected to lipopolysaccharide (LPS)-induced sepsis, and cardiac function was assessed in IRG1 knockout (IRG1-/-) and wild-type mice. Exogenous 4-octyl itaconate (4-OI) supplementation was also examined for its protective effects. In vitro, bone marrow-derived macrophages and RAW264.7 cells were treated with 4-OI following Nuclear factor, erythroid 2 like 2 (NRF2)-small interfering RNA administration to elucidate the underlying mechanisms. Our results indicate that IRG1 deficiency exacerbates myocardial injury during sepsis, while 4-OI administration preserves cardiac function and reduces inflammation. Mechanistic insights reveal that 4-OI activates the NRF2/HO-1 pathway, promoting macrophage polarization and attenuating inflammation. These findings underscore the protective role of the IRG1/itaconate axis in SIMD and suggest a therapeutic potential for 4-OI in modulating macrophage responses.

Keywords:  Itaconate; Macrophage polarization; Monocyte mobilization; NRF2; Septic myocardial injury

DOI:  https://doi.org/10.1186/s13062-024-00521-x
J Leukoc Biol. 2024 Oct 03. pii: qiae215. [Epub ahead of print]

Intracellular Methylglyoxal Accumulation in Classically Activated Mouse Macrophages is Mediated by HIF-1α.

Daniel Prantner, Stefanie N Vogel.

  Approximately one million cases of sepsis in the U.S.A. occur annually. The early phase of sepsis features dramatic changes in host metabolism and inflammation. While examining the effects of metabolic pathways on inflammation, we discovered that the highly reactive glycolytic metabolite, methylglyoxal (MG), accumulates intracellularly during classical activation of macrophages. Herein, we explored the role of glycolysis and the master regulator of glycolysis, Hypoxia-Inducing Factor-1α (HIF-1α), in inflammation and MG accumulation in mouse and human macrophages. To determine how HIF-1α regulates the inflammatory response of macrophages, we correlated HIF-1α stabilization with proinflammatory gene expression and MG-adduct accumulation in WT vs HIF1a-deficient macrophages treated with LPS or LPS+IFN-γ. A nearly complete loss of HIF-1α protein expression in response to the hypoxia mimetic, cobalt chloride, confirmed the phenotype of the HIF1a-deficient macrophages. Moreover, absence of HIF-1α was also associated with decreased MG accumulation. Increasing the glucose concentration in cultured macrophages was sufficient to cause accumulation of endogenous MG-adducts which correlated with increased Tnf and Il1b expression during classical activation. Use of the MG antagonist, aminoguanidine, led to a significant decrease in Tnf and Il1b expression in both mouse macrophages and in the THP-1 human macrophage cell line. Although off-target effects cannot be ruled out, these results are consistent with the possibility that MG regulates cytokine expression in classically activated macrophages. Collectively, this work suggests that HIF-1α stabilization is upstream of MG accumulation and that targeting the activity of HIF-1α in macrophages may be therapeutic during sepsis by limiting endogenous MG accumulation.

Keywords:  Innate immunity; cytokine regulation; inflammation; metabolism

DOI:  https://doi.org/10.1093/jleuko/qiae215
Int J Biol Macromol. 2024 Oct 01. pii: S0141-8130(24)07041-7. [Epub ahead of print] 136232

Selenoprotein o as a regulator of macrophage metabolism in selenium deficiency-induced lung inflammation.

Yongzhen Du, Yu Xia, Tong Xu, Haojie Hu, Yujiao He, Muyue Zhang, Shu Li.

  Selenium (Se) deficiency induces an inflammatory response in the lungs, but the underlying mechanisms are unknown. Selenoprotein O (SelO) is the largest selenoprotein in terms of molecular weight, yet its potential biological functions have yet to be characterized. Our study revealed that Se deficiency leads to an imbalance in the expression of pro-inflammatory "M1" macrophages and anti-inflammatory "M2" macrophages in alveolar macrophages (AMs) and interstitial macrophages (IMs) and contributed to the development of lung inflammation. Through the analysis of differentially expressed selenoproteins, we identified SelO as a potential regulator of the imbalance in pulmonary macrophage polarization caused by Se deficiency. In vitro experiments showed that SelO knockdown enhanced the polarization of M1 macrophages while suppressing that of M2 macrophages. In addition, SelO knockdown reprogrammed macrophage metabolism to glycolysis, disrupting oxidative phosphorylation (OXPHOS). Mechanistically, SelO primarily targets mitochondrial transcription factor A (TFAM), which plays a crucial role in the transcription and replication of mitochondrial DNA (mtDNA) and is essential for mitochondrial biogenesis and energy metabolism. The deficiency of SelO affects TFAM, resulting in its uncontrolled degradation, which compromises mitochondrial function and energy metabolism. In summary, the findings presented here offer significant theoretical insights into the physiological functions of SelO.

Keywords:  Macrophage polarization; Metabolic reprogramming; Pulmonary inflammation; Se deficiency; Selenoprotein O; TFAM

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136232
Curr Opin Immunol. 2024 Oct 01. pii: S0952-7915(24)00074-8. [Epub ahead of print]91 102484

Fuelling B cells: dynamic regulation of B cell metabolism.

Julia C Johnstone, Yavuz F Yazicioglu, Alexander J Clarke.

B cells experience extreme alterations in their metabolism throughout their life cycle, from naïve B cells, which have minimal activity, to germinal centre (GC) B cells, which proliferate at the fastest rate of all cells, to long-lived plasma cells with very high levels of protein production that can persist for decades. The underpinning of these transitions remains incompletely understood, and a key question is how utilisation of fuel source supports B cell metabolism. For example, GC B cells, unlike almost all rapidly proliferating cells, mainly use fatty acid oxidation rather than glycolysis. However, following differentiation to plasma cells, their metabolism switches towards a high rate of glucose consumption to aid antibody production. In this review, we discuss the key metabolic pathways in B cells, linking them to cellular signalling events and placing them in the context of disease and therapeutic potential.

DOI: https://doi.org/10.1016/j.coi.2024.102484
PLoS Pathog. 2024 Oct 04. 20(10): e1012188

Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.

Poornima Sankar, Ramon Bossardi Ramos, Jamie Corro, Lokesh K Mishra, Tanvir Noor Nafiz, Gunapati Bhargavi, Mohd Saqib, Sibongiseni K L Poswayo, Suraj P Parihar, Yi Cai, Selvakumar Subbian, Anil K Ojha, Bibhuti B Mishra.

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions.

DOI: https://doi.org/10.1371/journal.ppat.1012188
EMBO J. 2024 Sep 30.

Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.

Zining Wang, Lei Cui, Yanxun Lin, Bitao Huo, Hongxia Zhang, Chunyuan Xie, Huanling Zhang, Yongxiang Liu, Huan Jin, Hui Guo, Mengyun Li, Xiaojuan Wang, Penghui Zhou, Peng Huang, Jinyun Liu, Xiaojun Xia.

  The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.

Keywords:  Immunogenicity; Immunotherapy; Itaconate; Thimerosal

DOI:  https://doi.org/10.1038/s44318-024-00217-y
Clin Rheumatol. 2024 Oct 02.

TLR2 reprograms glucose metabolism in CD4+ T cells of rheumatoid arthritis patients to mediate cell hyperactivation and TNF-α secretion.

Qian Lin, Cheng Zhang, Huina Huang, Ziran Bai, Jiaqing Liu, Yan Zhang, Xia Li, Guan Wang.

   OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which activated CD4+ T cells participate in the disease process by inducing inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) on CD4+ T cells in RA patients, and to elucidate the underlying mechanisms by which TLR2 contributes to the pathogenesis of RA.
METHODS: Serum samples were collected from RA patients and healthy controls. Soluble TLR2 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to assess the TLR2 expression level, activation status, cytokine production, reactive oxygen species (ROS) levels, and glucose uptake capacity of CD4+ T cells. Quantitative polymerase chain reaction (qPCR) was used to measure the expression of enzymes associated with glucose and lipid metabolism. The concentration of lactic acid in the culture supernatant was determined using a dedicated detection kit.
RESULTS: RA patients had higher levels of TLR2 in their serum, which positively correlated with C-reactive protein and rheumatoid factor. The expression level of TLR2 in CD4+ T cells of RA patients was increased, and TLR2+ cells showed higher activation levels than TLR2- cells. Activation of TLR2 in CD4+ T cells of RA patients promoted their activation, TNF-α secretion, and increased production of ROS. Furthermore, TLR2 activation led to changes in enzymes related to glucose metabolism, causing a shift in glucose metabolism towards the pentose phosphate pathway. Blocking oxidative phosphorylation and the pentose phosphate pathway had varying effects on CD4+ T cell function.
CONCLUSION: TLR2 reprograms the glucose metabolism of CD4+ T cells in RA patients, contributing to the development of RA through ROS-mediated cell hyperactivation and TNF-α secretion. Key Points • TLR2 is upregulated in CD4+ T cells of RA patients and correlates with disease severity markers such as CRP and RF. • Activation of TLR2 in CD4+ T cells promotes cell activation, TNF-α secretion, and increased ROS production, contributing to the pathogenesis of RA. • TLR2 activates glucose metabolism in CD4+ T cells, shifting towards the pentose phosphate pathway, which may be a novel therapeutic target for RA treatment. • Blocking glucose metabolism and ROS production can reduce CD4 + T cell hyperactivation and TNF-α secretion, indicating potential therapeutic strategies for RA management.

Keywords:  CD4+ T cells; Glucose metabolism; Reactive oxygen species; Rheumatoid arthritis; TLR2

DOI:  https://doi.org/10.1007/s10067-024-07125-w
Viruses. 2024 Aug 30. pii: 1391. [Epub ahead of print]16(9):

Metabolic Dependency Shapes Bivalent Antiviral Response in Host Cells in Response to Poly:IC: The Role of Glutamine.

Grégorie Lebeau, Aurélie Paulo-Ramos, Mathilde Hoareau, Daed El Safadi, Olivier Meilhac, Pascale Krejbich-Trotot, Marjolaine Roche, Wildriss Viranaicken.

  The establishment of effective antiviral responses within host cells is intricately related to their metabolic status, shedding light on immunometabolism. In this study, we investigated the hypothesis that cellular reliance on glutamine metabolism contributes to the development of a potent antiviral response. We evaluated the antiviral response in the presence or absence of L-glutamine in the culture medium, revealing a bivalent response hinging on cellular metabolism. While certain interferon-stimulated genes (ISGs) exhibited higher expression in an oxidative phosphorylation (OXPHOS)-dependent manner, others were surprisingly upregulated in a glycolytic-dependent manner. This metabolic dichotomy was influenced in part by variations in interferon-β (IFN-β) expression. We initially demonstrated that the presence of L-glutamine induced an enhancement of OXPHOS in A549 cells. Furthermore, in cells either stimulated by poly:IC or infected with dengue virus and Zika virus, a marked increase in ISGs expression was observed in a dose-dependent manner with L-glutamine supplementation. Interestingly, our findings unveiled a metabolic dependency in the expression of specific ISGs. In particular, genes such as ISG54, ISG12 and ISG15 exhibited heightened expression in cells cultured with L-glutamine, corresponding to higher OXPHOS rates and IFN-β signaling. Conversely, the expression of viperin and 2'-5'-oligoadenylate synthetase 1 was inversely related to L-glutamine concentration, suggesting a glycolysis-dependent regulation, confirmed by inhibition experiments. This study highlights the intricate interplay between cellular metabolism, especially glutaminergic and glycolytic, and the establishment of the canonical antiviral response characterized by the expression of antiviral effectors, potentially paving the way for novel strategies to modulate antiviral responses through metabolic interventions.

Keywords:  OXPHOS; antiviral response; glycolysis; immunometabolism; metabolic reprogramming; mitochondrial respiration

DOI:  https://doi.org/10.3390/v16091391
Nat Commun. 2024 Oct 04. 15(1): 8624

MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.

Kelvin Ka-Lok Wu, Xiaofan Xu, Manyin Wu, Xiaomu Li, Moinul Hoque, Gloria Hoi Yee Li, Qizhou Lian, Kekao Long, Tongxi Zhou, Hailong Piao, Aimin Xu, Hannah Xiaoyan Hui, Kenneth King-Yip Cheng.

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.

DOI: https://doi.org/10.1038/s41467-024-53006-w
Nat Biomed Eng. 2024 Oct 04.

Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials.

Chima V Maduka, Axel D Schmitter-Sánchez, Ashley V Makela, Evran Ural, Katlin B Stivers, Hunter Pope, Maxwell M Kuhnert, Oluwatosin M Habeeb, Anthony Tundo, Mohammed Alhaj, Artem Kiselev, Shoue Chen, Alexis Donneys, Wade P Winton, Jenelle Stauff, Peter J H Scott, Andrew J Olive, Kurt D Hankenson, Ramani Narayan, Sangbum Park, Jennifer H Elisseeff, Christopher H Contag.

Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+ CX3CR1+ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ+ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment.

DOI: https://doi.org/10.1038/s41551-024-01260-0
J Leukoc Biol. 2024 Sep 28. pii: qiae211. [Epub ahead of print]

Immunometabolic Chaos in Septic Shock.

Deepmala Shrestha, Bishnu Pant, Sanjoy Roychowdhury, Anugraha Gandhirajan, Emily Cross, Mamta Chhabria, Seth Bauer, Margaret Jeng, Megan Mitchell, Omar Mehkri, Fatima Zaidi, Akash Ahuja, Xiaofeng Wang, Yuxin Wang, Christine McDonald, Michelle Longworth, Thaddeus Stappenbeck, George R Stark, Rachel Scheraga, Vidula Vachharajani.

  Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: 1. Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and 2. Plasma metabolomic profile by Metabolon. Inc. 3. We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: 1. The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. 2. A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. 3. In vitro exposure to five metabolites repressed while two metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.

Keywords:  Metabolism; Monocytes; Sepsis; Septic shock

DOI:  https://doi.org/10.1093/jleuko/qiae211
Cell Mol Biol Lett. 2024 Oct 01. 29(1): 129

The role and therapeutic potential of itaconate in lung disease.

Ruyuan He, Yifan Zuo, Ke Yi, Bohao Liu, Congkuan Song, Ning Li, Qing Geng.

  Lung diseases triggered by endogenous or exogenous factors have become a major concern, with high morbidity and mortality rates, especially after the coronavirus disease 2019 (COVID-19) pandemic. Inflammation and an over-activated immune system can lead to a cytokine cascade, resulting in lung dysfunction and injury. Itaconate, a metabolite produced by macrophages, has been reported as an effective anti-inflammatory and anti-oxidative stress agent with significant potential in regulating immunometabolism. As a naturally occurring metabolite in immune cells, itaconate has been identified as a potential therapeutic target in lung diseases through its role in regulating inflammation and immunometabolism. This review focuses on the origin, regulation, and function of itaconate in lung diseases, and briefly discusses its therapeutic potential.

Keywords:  Immunometabolism; Inflammation; Itaconate; Lung diseases; Macrophage; Metabolite

DOI:  https://doi.org/10.1186/s11658-024-00642-1
Immunol Res. 2024 Sep 30.

Anti-inflammatory effects of 1,7-dihydroxy-3,4-dimethoxyxanthone through inhibition of M1-phenotype macrophages via arginine/mitochondrial axis.

Xin Liu, Ting Wang, Ruoxuan Xiang, Huazhan Sun, Mengyan Zhao, Xiaojuan Ye, Yuyun Zhou, Guodong Wang, Yuyan Zhou.

  It is known that 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN), derived from Securidaca inappendiculata Hassk., exhibits anti-inflammatory and analgesic activities and inhibits M1 polarization of macrophages. However, its ability to alleviate inflammation induced by pro-inflammatory cytokines in THP-1 cells and its anti-inflammatory mechanisms remain unclear. THP-1 cells were treated with phorbol 12-myristate-13-acetate to differentiate and divided into three groups. They were stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). The toxicity of XAN was assessed using Cell Counting Kit-8, and the expression of various genes and proteins was analyzed using real-time quantitative polymerase chain reaction, flow cytometry, and western blotting. Transmission electron microscopy was used to observe changes in mitochondrial structure. XAN at concentrations ≤ 10 µg/mL did not affect THP-1 cell viability and reduced the mRNA expression of pro-inflammatory factors, including interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), NOD-like receptor thermal protein domain protein 3 (NLRP3), and tumor necrosis factor-α (TNF-α). XAN also increased the levels of anti-inflammatory factors, including chemokine ligand 22, mannose receptor (CD206), IL-10, peroxisome proliferator-activated receptor-γ, and transglutaminase 2. Additionally, XAN downregulated the expression of inflammation-related proteins iNOS, NLRP3, and IL-1β; significantly increased the expression of arginase 1, ornithine decarboxylase, and arginine metabolism-related proteins and genes; inhibited mitochondrial damage; and reduced reactive oxygen species (ROS) generation. XAN enhanced the arginine metabolism pathway, prevented mitochondrial damage, reduced ROS levels, and provided an effective defensive response against LPS/IFN-γ-induced inflammation.

Keywords:  Arginine metabolism; Macrophage polarization; Mitochondrial metabolic reprogramming; ROS

DOI:  https://doi.org/10.1007/s12026-024-09538-w
J Immunol. 2024 Oct 04. pii: ji2400127. [Epub ahead of print]

Immunometabolic Mechanisms of LANCL2 in CD4+ T Cells and Phagocytes Provide Protection from Systemic Lupus Erythematosus.

Andrew Leber, Raquel Hontecillas, Nuria Tubau-Juni, Sarah N Fitch, Josep Bassaganya-Riera.

Lanthionine synthetase C-like 2 (LANCL2) is an immunoregulatory therapeutic target for autoimmune diseases. NIM-1324 is an investigational new drug aimed at addressing the unmet clinical needs of patients with systemic lupus erythematosus (SLE) by targeting the LANCL2 immunometabolic pathway. In R848 and bm12 adoptive transfer models of systemic inflammation that share pathologies with SLE, Lancl2-/- mice experienced greater mortality, increased spleen weight, and reduced CD25hi FOXP3+ CD4+ regulatory T cells compared with the wild type. Conversely, treatment with NIM-1324 in the wild type increased CD25hi FOXP3+ regulatory T cells while reducing inflammatory IL-17+ and IL-21+ CD4+ T cell subsets in the spleen. In traditional mouse models of SLE (NZB/W F1 and MRL/lpr), oral treatment with NIM-1324 protected against weight loss and proteinuria, decreased anti-dsDNA titers, and provided similar changes to the CD4+ T cell compartment in the spleen. The pharmacological activation of LANCL2 by NIM-1324 rescued hypocomplementemia, reduced kidney histopathological scores, and decreased blood IFN response genes and inflammatory cytokines. The loss of LANCL2 in phagocytes impairs phagosome processing, leading to increased uptake of material and inflammatory cytokine production, yet decreased markers of endosomal maturation, phagosome turnover, and lysozyme activity. Treatment with NIM-1324 increases metabolic and lysozyme activity in the phagosome, providing support for increased markers of early phagosome function. This efficacy translated to human PBMCs from patients with SLE, because ex vivo treatment with NIM-1324 resulted in reduced levels of IFN-α, IL-6, and IL-8. Consequently, the activation of LANCL2 effectively modulates CD4+ T cell differentiation and phagocyte activation, supporting immune tolerance in SLE.

DOI: https://doi.org/10.4049/jimmunol.2400127
Biochim Biophys Acta Mol Basis Dis. 2024 Oct 02. pii: S0925-4439(24)00522-2. [Epub ahead of print] 167528

Myeloid PGC1β attenuates high-fat-diet induced inflammation via mitochondrial fission/mtDNA/Nlrp3 pathway.

En Li, Jiajia Ji, Gaoyang Zong, Hao Liu, Yue Sun, Liangliang Wei, Zhihao Xia, Xiaoyu Yang, Dageng Huang, Yan Zhang.

  Peroxisome proliferator-activated receptor gamma coactivators 1β (PGC1β) is essential in mitochondrial oxidative phosphorylation and alternative macrophages activation. To determine the contribution of PGC1β in obesity induced inflammation, Ppargc1b (PGC1β coding gene) myeloid conditional knockout mice (cKO) were fed with high fat diet (HFD) to examine the following effects. We found that HFD-fed cKO mice gained more fat with increased serum triglyceride (TG), low density lipoprotein (LDL), adiponectin, and leptin. Adipogenesis was stimulated while lipolysis was retarded in HFD-fed cKO mice adipose. Gluconeogenesis, lipogenesis, and fatty acid uptake were provoked while lipolysis was inhibited in HFD-fed cKO liver. Serum alanine transaminase (ALT) level, indicating fatty liver, also increased. Inflammatory cytokine including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 was elevated in cKO mice, accompanied with glucose intolerant and insulin resistance. Energy expenditure was decreased in HFD-fed cKO mice. Further evidence showed that cKO macrophages were prone to repolarize into M1 inflammatory type in vitro. In addition to mitochondrial biogenesis and oxidative respiration, PGC1β also modulated mitochondrial fission and cytosolic mitochondrial DNA (mtDNA) release, contributing to NLR family pyrin domain containing 3 (Nlrp3) inflammasome priming and activation. Treatment of mitochondrial fission inhibitor abolished the increased mRNA levels of Nlrp3 and IL-1β induced by PGC1β depletion. Nlrp3 knockdown restored the induced IL-1β mRNA expression by PGC1β deficiency. Myeloid PGC1β regulated adipocyte adipogenesis and lipolysis. PGC1β loss-of-function and mtDNA abundance correlated with obesity and diabetes. These observations uncovered the protective role of PGC1β against obesity induced systemic inflammation. Enhancing myeloid PGC1β function may be a potential strategy for the intervention of obesity and related diseases.

Keywords:  Inflammation; Macrophage; Mitochondria; PGC1β

DOI:  https://doi.org/10.1016/j.bbadis.2024.167528
Biochem Biophys Res Commun. 2024 Sep 24. pii: S0006-291X(24)01274-9. [Epub ahead of print]734 150738

Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion.

Min Liu, Xinyue Fu, Qinghe Yi, Enhong Xu, Longbao Dong.

  CD8+ T cells play a crucial role in anti-tumor immunity, but their function can be impaired by exhaustion induced by prolonged antigen stimulation. Mitochondrial dysfunction, a hallmark of the tumor microenvironment (TME), has been linked to various pathologies, but its specific role in CD8+ T cell exhaustion remains underexplored. Here, we established an in vitro model of CD8+ T cell exhaustion by co-culturing OVA-specific OT1 CD8+ T cells with OVA-expressing MC38 tumor cells. Next, we investigated the impact of mitochondrial dysfunction on exhaustion using pharmacological inhibitors targeting the electron transport chain. The role of the mitochondrial complex I component NDUFA10 was further examined through genetic knockout in CD8+ T cells using CRISPR-Cas9. Inhibition of the mitochondrial electron transport chain significantly accelerated CD8+ T cell exhaustion in vitro. Knockout of NDUFA10 in CD8+ T cells led to enhanced tumor growth and increased exhaustion of tumor-infiltrating CD8+ T cells in a Rag1-/- tumor-bearing transfer model. This study highlights the critical role of mitochondrial function in regulating CD8+ T cell exhaustion and anti-tumor activity, providing new insights into the metabolic underpinnings of immune dysfunction in cancer.

Keywords:  CD8(+) T cell; Exhaustion; Mitochondrion

DOI:  https://doi.org/10.1016/j.bbrc.2024.150738
Front Immunol. 2024 ;15 1432334

Aconitate decarboxylase 1 mediates the acute airway inflammatory response to environmental exposures.

Aaron D Schwab, Amy J Nelson, Angela M Gleason, Oliver W Schanze, Todd A Wyatt, Dhananjay D Shinde, Peng Xiao, Vinai C Thomas, Chittibabu Guda, Kristina L Bailey, Tammy Kielian, Geoffrey M Thiele, Jill A Poole.

   Background: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung disease. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Aconitate decarboxylase 1 (Acod1) was one of the most upregulated genes following LPS (vs. saline) exposure of murine whole lungs with transcriptomic profiling of sorted lung monocyte/macrophage subpopulations also highlighting its significance. Given monocyte/macrophage activation can be tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator ACOD1 in environmental exposure-induced lung inflammation.
Methods: Wild-type (WT) mice were intratracheally (i.t.) instilled with 10 μg of LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 h post-exposure. Next, WT and Acod1-/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline, whereupon serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Invasive lung function testing was performed 3 h post-LPS with WT and Acod1-/- mice.
Results: Acod1-/- mice treated with LPS demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4+ T cells, decreased BALF and lung levels of TNF-α, and decreased BALF CXCL1 compared to WT animals. In comparison, Acod1-/- mice treated with ODE demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B-cell infiltrates with decreased BALF levels of TNF-α and IL-6 and decreased lung CXCL1 vs. WT animals. Mediators of tissue remodeling (TIMP1, MMP-8, MMP-9) were also decreased in the LPS-exposed Acod1-/- mice, with MMP-9 also reduced in ODE-exposed Acod1-/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyperresponsiveness in Acod1-/- animals.
Conclusion: Acod1 is robustly upregulated in the lungs following LPS exposure and encodes a key immunometabolic regulator. ACOD1 mediates the proinflammatory response to acute inhaled environmental LPS and organic dust exposure-induced lung inflammation.

Keywords:  ACOD1; endotoxin; environmental health; immunometabolism; inhalation; macrophages; organic dust

DOI:  https://doi.org/10.3389/fimmu.2024.1432334
Cell Death Discov. 2024 Sep 30. 10(1): 417

Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.

Elisabet Cuyàs, Stefano Pedarra, Sara Verdura, Miguel Angel Pardo, Roderic Espin Garcia, Eila Serrano-Hervás, Àngela Llop-Hernández, Eduard Teixidor, Joaquim Bosch-Barrera, Eugeni López-Bonet, Begoña Martin-Castillo, Ruth Lupu, Miguel Angel Pujana, Josep Sardanyès, Tomás Alarcón, Javier A Menendez.

Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.

DOI: https://doi.org/10.1038/s41420-024-02184-z
Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2404841121

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance.

Abhimanyu, Santiago Carrero Longlax, Tomoki Nishiguchi, Malik Ladki, Daanish Sheikh, Amera L Martinez, Emily M Mace, Sandra L Grimm, Thaleia Caldwell, Alexandra Portillo Varela, Rajagopal V Sekhar, Anna M Mandalakas, Mandla Mlotshwa, Sibuse Ginidza, Jeffrey D Cirillo, Robert S Wallis, Mihai G Netea, Reinout van Crevel, Cristian Coarfa, Andrew R DiNardo.

  Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.

Keywords:  DNA methylation; Rheostat; immune tolerance; sepsis; tuberculosis

DOI:  https://doi.org/10.1073/pnas.2404841121
Curr Opin Immunol. 2024 Oct 01. pii: S0952-7915(24)00075-X. [Epub ahead of print]91 102485

Immunometabolic regulation of germinal centers and its implications for aging.

Daehong Kim, Jaemin Kim, Hyeonuk Yeo, Yeonseok Chung.

Aging, metabolism, and immunity have long been considered distinct domains. Aging is primarily associated with the gradual decline of physiological functions, metabolism regulates energy production and maintains cellular processes, and the immune system manages innate and adaptive responses against pathogens and vaccines. However, recent studies have revealed that these three systems are intricately interconnected, collectively influencing an individual's response to stress and disease. This review explores the interplay between immunometabolism, T follicular helper cells, B cells, and aging, focusing on how these interactions impact immune function in the elderly.

DOI: https://doi.org/10.1016/j.coi.2024.102485
Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2406492121

Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.

Alan H Diercks, Irina S Podolskaia, Tara A Murray, Ana N Jahn, Dat Mai, Dong Liu, Lynn M Amon, Yoshimi Nakagawa, Hitoshi Shimano, Alan Aderem, Elizabeth S Gold.

  Toll-like receptors (TLRs) on macrophages sense microbial components and trigger the production of numerous cytokines and chemokines that mediate the inflammatory response to infection. Although many of the components required for the activation of the TLR pathway have been identified, the mechanisms that appropriately regulate the magnitude and duration of the response and ultimately restore homeostasis are less well understood. Furthermore, a growing body of work indicates that TLR signaling reciprocally interacts with other fundamental cellular processes, including lipid metabolism but only a few specific molecular links between immune signaling and the macrophage lipidome have been studied in detail. Oxysterol-binding protein (Osbp) is the founding member of a family of lipid-binding proteins with diverse functions in lipid sensing, lipid transport, and cell signaling but its role in TLR responses is not well defined. Here, we demonstrate that altering the state of Osbp with its natural ligand, 25-hydroxycholesterol (25HC), or pharmacologically, sustains and thereby amplifies Tlr4-induced cytokine production in vitro and in vivo. CRISPR-induced knockdown of Osbp abrogates the ability of these ligands to sustain TLR responses. Lipidomic analysis suggested that the effect of Osbp on TLR signaling may be mediated by alterations in triglyceride production and treating cells with a Dgat1 inhibitor, which blocks triglyceride production and completely abrogates the effect of Osbp on TLR signaling. Thus, Osbp is a sterol sensor that transduces perturbations of the lipidome to modulate the resolution of macrophage inflammatory responses.

Keywords:  25-hydroxycholesterol; Osbp; immunometabolism; macrophage; toll-like receptor

DOI:  https://doi.org/10.1073/pnas.2406492121