bims-imicid 2024-09-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–09–08
34 papers selected by
Dylan Ryan, University of Cambridge

Immunometabolic effects of lactate on humoral immunity in healthy individuals of different ages.
MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.
Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming.
Metabolic immaturity and breastmilk bile acid metabolites are central determinants of heightened newborn vulnerability to norovirus diarrhea.
Regulation of host metabolism and defense strategies to survive neonatal infection.
Acidity induces durable enhancement of Treg cell suppressive functions for tumor immune evasion.
Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.
PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.
Metabolic Control of Microglia.
Postbiotic impact on host metabolism and immunity provides therapeutic potential in metabolic disease.
Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.
Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion.
Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment.
Reprogramming macrophage metabolism following myocardial infarction: A neglected piece of a therapeutic opportunity.
Innate immunity in peripheral tissues is differentially impaired under normal and endotoxic conditions in aging.
Classical swine fever virus inhibits serine metabolism-mediated antiviral immunity by deacetylating modified PHGDH.
Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.
A new paradigm in intracellular immunology: Mitochondria emerging as leading immune organelles.
Glycolytic reprogramming governs crystalline silica-induced pyroptosis and inflammation through promoting lactylation modification.
Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity.
The role of lipids in regulating macrophage antifungal immunity.
The glycolytic reaction PGAM unexpectedly restrains Th17 pathogenicity and Th17-dependent autoimmunity.
A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD.
TREM2 Impairs Glycolysis to Interrupt Microglial M1 Polarization and Inflammation via JAK2/STAT3 Axis.
Engaging natural regulatory myeloid cells to restrict T-cell hyperactivation-induced liver inflammation via extracellular vesicle-mediated purine metabolism regulation.
Succinate activates UCP2 to suppress neuroinflammation and confer protection following intracerebral hemorrhage.
Effects of Fasting on THP1 Macrophage Metabolism and Inflammatory Profile.
Helminth-derived metabolites induce tolerogenic functional, metabolic, and transcriptional signatures in dendritic cells that attenuate experimental colitis.
GAPDH-Silence Microsphere via Reprogramming Macrophage Metabolism and eradicating Bacteria for Diabetic infection bone regeneration.
Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.
Obesity alters the macrophages' response to Leishmania major in C57BL/6 mice.
Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.
Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming.
H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response.

Nat Commun. 2024 Aug 30. 15(1): 7515

Immunometabolic effects of lactate on humoral immunity in healthy individuals of different ages.

Maria Romero, Kate Miller, Andrew Gelsomini, Denisse Garcia, Kevin Li, Dhananjay Suresh, Daniela Frasca.

Aging is characterized by chronic systemic inflammation and metabolic changes. We compare the metabolic status of B cells from young and elderly donors and found that aging is associated with higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects age-associated expansion of pro-inflammatory B cells, is found associated with higher secretion of lactate and autoimmune antibodies after in vitro stimulation. B cells from elderly individuals induce in vitro polarization of CD4+ T cells from young individuals into pro-inflammatory CD4+ T cells through metabolic pathways mediated by lactate, which can be inhibited by targeting lactate enzymes and transporters, as well as signaling pathways supporting anaerobic glycolysis. Lactate also induces immunosenescent B cells that are glycolytic, express transcripts for multiple pro-inflammatory molecules, and are characterized by a higher metabolic status. These results altogether may have relevant clinical implications and suggest alternative targets for therapeutic interventions in the elderly and patients with inflammatory conditions and diseases.

DOI: https://doi.org/10.1038/s41467-024-51207-x
Cell Rep. 2024 Aug 28. pii: S2211-1247(24)01033-7. [Epub ahead of print]43(9): 114682

MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.

Hui-Ru Chen, Yidan Sun, Gerhard Mittler, Tobias Rumpf, Maria Shvedunova, Rudolf Grosschedl, Asifa Akhtar.

  Signaling-dependent changes in protein phosphorylation are critical to enable coordination of transcription and metabolism during macrophage activation. However, the role of acetylation in signal transduction during macrophage activation remains obscure. Here, we identify the redox signaling regulator peroxiredoxin 1 (PRDX1) as a substrate of the lysine acetyltransferase MOF. MOF acetylates PRDX1 at lysine 197, preventing hyperoxidation and thus maintaining its activity under stress. PRDX1 K197ac responds to inflammatory signals, decreasing rapidly in mouse macrophages stimulated with bacterial lipopolysaccharides (LPSs) but not with interleukin (IL)-4 or IL-10. The LPS-induced decrease of PRDX1 K197ac elevates cellular hydrogen peroxide accumulation and augments ERK1/2, but not p38 or AKT, phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Our work reveals a regulatory role for redox protein acetylation in signal transduction and coordinating metabolic and transcriptional programs during inflammatory macrophage activation.

Keywords:  CP: Immunology; CP: Molecular biology; ERK1/2; MAPK; glycolytic metabolism; histone H3 serine 28 phosphorylation; lysine acetyltransferase MOF; macrophage activation; peroxiredoxin; protein acetylation; redox signaling; signal transduction

DOI:  https://doi.org/10.1016/j.celrep.2024.114682
Immunity. 2024 Aug 23. pii: S1074-7613(24)00407-2. [Epub ahead of print]

Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming.

Dongkyun Kim, Giha Kim, Rongzhen Yu, Juyeun Lee, Sohee Kim, Mia R Gleason, Kevin Qiu, Elena Montauti, Li Lily Wang, Deyu Fang, Jaehyuk Choi, Navdeep S Chandel, Samuel Weinberg, Booki Min.

  Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.

Keywords:  Lag3; Myc; Treg cells; autoimmunity; metabolism

DOI:  https://doi.org/10.1016/j.immuni.2024.08.008
Cell Host Microbe. 2024 Aug 21. pii: S1931-3128(24)00290-7. [Epub ahead of print]

Metabolic immaturity and breastmilk bile acid metabolites are central determinants of heightened newborn vulnerability to norovirus diarrhea.

Amy M Peiper, Joyce Morales Aparicio, Zhengzheng Hu, Lufuno Phophi, Emily W Helm, Rebecca J Rubinstein, Matthew Phillips, Caroline G Williams, Saravanan Subramanian, Michael Cross, Neha Iyer, Quyen Nguyen, Rachel Newsome, Christian Jobin, Stephanie N Langel, Filemon Bucardo, Sylvia Becker-Dreps, Xiao-Di Tan, Paul A Dawson, Stephanie M Karst.

  The pathogenic outcome of enteric virus infections is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors, with metabolites serving as a key mediator. Noroviruses bind bile acid metabolites, which are produced by the host and then modified by commensal bacteria. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Working in an infant mouse model of norovirus infection, we demonstrate that microbiota and their bile acid metabolites protect from norovirus diarrhea, whereas host bile acids promote disease. We also find that maternal bile acid metabolism determines the susceptibility of newborn mice to norovirus diarrhea during breastfeeding. Finally, targeting maternal and neonatal bile acid metabolism can protect newborn mice from norovirus disease. In summary, neonatal metabolic immaturity and breastmilk bile acids are central determinants of heightened newborn vulnerability to norovirus disease.

Keywords:  ASBT; bile acids; breastmilk metabolites; enteromammary; gut-mammary; microbial metabolites; microbiota; neonatal infections; newborn infections; norovirus

DOI:  https://doi.org/10.1016/j.chom.2024.08.003
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 29. pii: S0925-4439(24)00476-9. [Epub ahead of print]1870(8): 167482

Regulation of host metabolism and defense strategies to survive neonatal infection.

Ziyuan Wu, Nguyen Tran Nam Tien, Ole Bæk, Jingren Zhong, Björn Klabunde, Tinh Thu Nguyen, Nguyen Thi Hai Yen, Nguyen Phuoc Long, Duc Ninh Nguyen.

  Two distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection.

Keywords:  Defense strategies; Disease resistance; Disease tolerance; Glycolysis; Mitochondrial activity; Neonatal infection

DOI:  https://doi.org/10.1016/j.bbadis.2024.167482
Mol Immunol. 2024 Aug 29. pii: S0161-5890(24)00160-3. [Epub ahead of print]174 57-68

Acidity induces durable enhancement of Treg cell suppressive functions for tumor immune evasion.

Nikita L Mani, Samuel E Weinberg, Shuvam Chaudhuri, Elena Montauti, Amy Tang, Radhika Iyer, Deyu Fang.

  The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (Treg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral Treg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nTreg cells, but not iTreg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nTreg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nTreg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nTreg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nTreg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nTreg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nTreg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion.

Keywords:  Acidity; Formate; Lactate; Oxidative phosphorylation; Suppression; T(reg) cells

DOI:  https://doi.org/10.1016/j.molimm.2024.08.004
J Clin Invest. 2024 Sep 03. pii: e177606. [Epub ahead of print]134(17):

Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.

Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M Mangarin, Jonathan F Khan, Mamadou A Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub.

  Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Keywords:  Cancer immunotherapy; Glucose metabolism; Immunology; Metabolism; Pharmacology

DOI:  https://doi.org/10.1172/JCI177606
Immunity. 2024 Aug 22. pii: S1074-7613(24)00376-5. [Epub ahead of print]

PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.

Yu Ping, Jiqi Shan, Haiming Qin, Feng Li, Jiao Qu, Ru Guo, Dong Han, Wei Jing, Yaqing Liu, Jinyan Liu, Zhangnan Liu, Jieyao Li, Dongli Yue, Feng Wang, Liping Wang, Bin Zhang, Bo Huang, Yi Zhang.

  The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

Keywords:  CD8(+) T cell; PD-1 signaling; PLPP1; anti-PD-1 therapy; antitumor immunity; ferroptosis; lipid peroxidation; phospholipid metabolism; tumor microenvironment; unsaturated fatty acid

DOI:  https://doi.org/10.1016/j.immuni.2024.08.003
Adv Neurobiol. 2024 ;37 607-622

Metabolic Control of Microglia.

Monica Emili Garcia-Segura, Stefano Pluchino, Luca Peruzzotti-Jametti.

  Microglia, immune sentinels of the central nervous system (CNS), play a critical role in maintaining its health and integrity. This chapter delves into the concept of immunometabolism, exploring how microglial metabolism shapes their diverse immune functions. It examines the impact of cell metabolism on microglia during various CNS states, including homeostasis, development, aging, and inflammation. Particularly in CNS inflammation, the chapter discusses how metabolic rewiring in microglia can initiate, resolve, or perpetuate inflammatory responses. The potential of targeting microglial metabolism as a therapeutic strategy for chronic CNS disorders with prominent innate immune cell activation is also explored.

Keywords:  Immunometabolism; Lipid metabolism; Metabolic reprogramming; Mitochondria

DOI:  https://doi.org/10.1007/978-3-031-55529-9_34
Endocr Rev. 2024 Sep 05. pii: bnae025. [Epub ahead of print]

Postbiotic impact on host metabolism and immunity provides therapeutic potential in metabolic disease.

Han Fang, Rodrigo Rodrigues E-Lacerda, Nicole G Barra, Dana Kukje Zada, Nazli Robin, Alina Mehra, Jonathan D Schertzer.

  The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds such as lipopolysaccharides, muropeptides can have opposing effects on endocrine control of host metabolism where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites such as short chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.

Keywords:  gut microbiota; inflammation; metabolic diseases; metabolism; postbiotics

DOI:  https://doi.org/10.1210/endrev/bnae025
Microbiol Mol Biol Rev. 2024 Sep 04. e0017122

Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.

Harshini Weerasinghe, Helen Stölting, Adam J Rose, Ana Traven.

  SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes.

Keywords:  Aspergillus; Candida; Cryptococcus; disease tolerance; fungal infection; fungal pathogens; immunity; immunometabolism; metabolic disease; metabolism

DOI:  https://doi.org/10.1128/mmbr.00171-22
Cell Signal. 2024 Aug 30. pii: S0898-6568(24)00338-3. [Epub ahead of print]123 111370

Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion.

Fan Ao-Di, Lin Han-Qing, Wang Xi-Zheng, Yang Ke, Guo Hong-Xin, Zhang Hai-Xia, Fan Guan-Wei, Li-Lan.

  Acute myocardial infarction (AMI) is the leading cause of death worldwide, and reperfusion therapy is a critical therapeutic approach to reduce myocardial ischemic injury and minimize infarct size. However, ischemia/reperfusion (I/R) itself also causes myocardial injury, and inflammation is an essential mechanism by which it leads to myocardial injury, with macrophages as crucial immune cells in this process. Macrophages are innate immune cells that maintain tissue homeostasis, host defence during pathogen infection, and repair during tissue injury. During the acute phase of I/R, M1-type macrophages generate a pro-inflammatory milieu, clear necrotic myocardial tissue, and further recruit mononuclear (CCR2+) macrophages. Over time, the reparative (M2 type) macrophages gradually became dominant. In recent years, metabolic studies have shown a clear correlation between the metabolic profile of macrophages and their phenotype and function. M1-type macrophages are mainly characterized by glycolytic energy supply, and their tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS) processes are impaired. In contrast, M2 macrophages rely primarily on OXPHOS for energy. Changing the metabolic profile of macrophages can alter the macrophage phenotype. Altered energy pathways are also present in macrophages during I/R, and intervention in this process contributes to earlier and greater M2 macrophage infiltration, which may be a potential target for the treatment of myocardial I/R injury. Therefore, this paper mainly reviews the characteristics of macrophage energy metabolism alteration and phenotypic transition during I/R and its mechanism of mediating myocardial injury to provide a basis for further research in this field.

Keywords:  Macrophage; Metabolic reprogramming; Myocardial ischemia-reperfusion

DOI:  https://doi.org/10.1016/j.cellsig.2024.111370
Biomark Res. 2024 Sep 03. 12(1): 96

Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment.

Haixia Zhang, Shizhen Li, Dan Wang, Siyang Liu, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen.

  Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies.

Keywords:  Immune evasion; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40364-024-00646-1
Int Immunopharmacol. 2024 Aug 31. pii: S1567-5769(24)01540-6. [Epub ahead of print]142(Pt A): 113019

Reprogramming macrophage metabolism following myocardial infarction: A neglected piece of a therapeutic opportunity.

Baoping Xie, Jiahua Li, Yanmei Lou, Qi Chen, Ying Yang, Rong Zhang, Zhongqiu Liu, Liu He, Yuanyuan Cheng.

  Given the global prevalence of myocardial infarction (MI) as the leading cause of mortality, there is an urgent need to devise novel strategies that target reducing infarct size, accelerating cardiac tissue repair, and preventing detrimental left ventricular (LV) remodeling. Macrophages, as a predominant type of innate immune cells, undergo metabolic reprogramming following MI, resulting in alterations in function and phenotype that significantly impact the progression of MI size and LV remodeling. This article aimed to delineate the characteristics of macrophage metabolites during reprogramming in MI and elucidate their targets and functions in cardioprotection. Furthermore, we summarize the currently proposed regulatory mechanisms of macrophage metabolic reprogramming and identify the regulators derived from endogenous products and natural small molecules. Finally, we discussed the challenges of macrophage metabolic reprogramming in the treatment of MI, with the goal of inspiring further fundamental and clinical research into reprogramming macrophage metabolism and validating its potential therapeutic targets for MI.

Keywords:  Endogenous metabolites; Macrophage; Metabolism reprogramming; Myocardial infarction

DOI:  https://doi.org/10.1016/j.intimp.2024.113019
Front Immunol. 2024 ;15 1357444

Innate immunity in peripheral tissues is differentially impaired under normal and endotoxic conditions in aging.

Ji Yeon Noh, Hye Won Han, Da Mi Kim, Erin D Giles, Yuhua Z Farnell, Gus A Wright, Yuxiang Sun.

  Chronic low-grade inflammation is a hallmark of aging, aka "inflammaging", which is linked to a wide range of age-associated diseases. Immune dysfunction increases disease susceptibility, and increases morbidity and mortality of aging. Innate immune cells, including monocytes, macrophages and neutrophils, are the first responders of host defense and the key mediators of various metabolic and inflammatory insults. Currently, the understanding of innate immune programming in aging is largely fragmented. Here we investigated the phenotypic and functional properties of innate immune cells in various peripheral tissues of young and aged mice under normal and endotoxic conditions. Under the steady state, aged mice showed elevated pro-inflammatory monocytes/macrophages in peripheral blood, adipose tissue, liver, and colon. Under lipopolysaccharide (LPS)-induced inflammatory state, the innate immune cells of aged mice showed a different response to LPS stimulus than that of young mice. LPS-induced immune responses displayed differential profiles in different tissues and cell types. In the peripheral blood, when responding to LPS, the aged mice showed higher neutrophils, but lower pro-inflammatory monocytes than that in young mice. In the peritoneal fluid, while young mice exhibited significantly elevated pro-inflammatory neutrophils and macrophages in response to LPS, aged mice exhibited decreased pro-inflammatory neutrophils and variable cytokine responses in macrophages. In the adipose tissue, LPS induced less infiltrated neutrophils but more infiltrated macrophages in old mice than young mice. In the liver, aged mice showed a more robust increase of pro-inflammatory macrophages compared to that in young mice under LPS stimulation. In colon, macrophages showed relatively mild response to LPS in both young and old mice. We have further tested bone-marrow derived macrophages (BMDM) from young and aged mice, we found that BMDM from aged mice have impaired polarization, displaying higher expression of pro-inflammatory markers than those from young mice. These data collectively suggest that innate immunity in peripheral tissues is impaired in aging, and the dysregulation of immunity is tissue- and cell-dependent. Our findings in the rodent model underscore the complexity of aging immunity. Further investigation is needed to determine whether the immune profile observed in aged mice is applicable in age-associated diseases in humans.

Keywords:  aging; immunometabolism; inflammaging; innate immunity; macrophages; monocytes; neutrophils

DOI:  https://doi.org/10.3389/fimmu.2024.1357444
mBio. 2024 Aug 29. e0209724

Classical swine fever virus inhibits serine metabolism-mediated antiviral immunity by deacetylating modified PHGDH.

Xiaowen Li, Yaoyao Huang, Xueyi Liu, Lihong Zhang, Xinyan Wang, Feifan Zhao, Linke Zou, Keke Wu, Wenxian Chen, Yuwei Qin, Sen Zeng, Bingke Li, Yintao He, Yiwan Song, Zhaoyao Li, Jindai Fan, Mingqiu Zhao, Lin Yi, Hongxing Ding, Shuangqi Fan, Jinding Chen.

  Classical swine fever virus (CSFV), an obligate intracellular pathogen, hijacks cellular metabolism to evade immune surveillance and facilitate its replication. The precise mechanisms by which CSFV modulates immune metabolism remain largely unknown. Our study reveals that CSFV infection disrupts serine metabolism, which plays a crucial role in antiviral immunity. Notably, we discovered that CSFV infection leads to the deacetylation of PHGDH, a key enzyme in serine metabolism, resulting in autophagic degradation. This deacetylation impairs PHGDH's enzymatic activity, reduces serine biosynthesis, weakens innate immunity, and promotes viral proliferation. Molecularly, CSFV infection induces the association of HDAC3 with PHGDH, leading to deacetylation at the K364 site. This modification attracts the E3 ubiquitin ligase RNF125, which facilitates the addition of K63-linked ubiquitin chains to PHGDH-K364R. Subsequently, PHGDH is targeted for lysosomal degradation by p62 and NDP52. Furthermore, the deacetylation of PHGDH disrupts its interaction with the NAD+ substrate, destabilizing the PHGDH-NAD complex, impeding the active site, and thereby inhibiting de novo serine synthesis. Additionally, our research indicates that deacetylated PHGDH suppresses the mitochondria-MAVS-IRF3 pathway through its regulatory effect on serine metabolism, leading to decreased IFN-β production and enhanced viral replication. Overall, our findings elucidate the complex interplay between CSFV and serine metabolism, revealing a novel aspect of viral immune evasion through the lens of immune metabolism.
IMPORTANCE: Classical swine fever (CSF) seriously restricts the healthy development of China's aquaculture industry, and the unclear pathogenic mechanism and pathogenesis of classical swine fever virus (CSFV) are the main obstacle to CSF prevention, control, and purification. Therefore, it is of great significance to explore the molecular mechanism of CSFV and host interplay, to search for the key signaling pathways and target molecules in the host that regulate the replication of CSFV infection, and to elucidate the mechanism of action of host immune dysfunction and immune escape due to CSFV infection for the development of novel CSFV vaccines and drugs. This study reveals the mechanism of serine metabolizing enzyme post-translational modifications and antiviral signaling proteins in the replication of CSFV and enriches the knowledge of CSFV infection and immune metabolism.

Keywords:  PHGDH; acetylation; classical swine fever virus; innate immunity; serine metabolism

DOI:  https://doi.org/10.1128/mbio.02097-24
J Allergy Clin Immunol. 2024 Aug 27. pii: S0091-6749(24)00867-4. [Epub ahead of print]

Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.

Sinéad Ryan, Louise Crowe, Sofía N Almeida Cruz, Matthew D Galbraith, Carol O'Brien, Juliet A Hammer, Ronan Bergin, Shauna K Kellett, Gary E Markey, Taylor M Benson, Olga Fagan, Joaquin M Espinosa, Niall Conlon, Claire L Donohoe, Susan McKiernan, Andrew E Hogan, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson.

   BACKGROUND: Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted the absence of hypoxia signaling through HIF-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy.
OBJECTIVES: Herein, we sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE.
METHODS: In RNA-sequencing derived from EoE patient biopsies, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Bioenergetics analysis using Seahorse was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were employed to delineate metabolic dependency mechanisms required for epithelial differentiation.
RESULTS: Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsies. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells which portray a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacological glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor DMOG resulted in restored expression of epithelial differentiation markers.
CONCLUSIONS: An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.

Keywords:  Eosinophilic esophagitis; HIF-1α; differentiation; glycolysis

DOI:  https://doi.org/10.1016/j.jaci.2024.07.030
Redox Biol. 2024 Aug 29. pii: S2213-2317(24)00309-4. [Epub ahead of print]76 103331

A new paradigm in intracellular immunology: Mitochondria emerging as leading immune organelles.

Keman Xu, Fatma Saaoud, Ying Shao, Yifan Lu, Qiaoxi Yang, Xiaohua Jiang, Hong Wang, Xiaofeng Yang.

  Mitochondria, traditionally recognized as cellular 'powerhouses' due to their pivotal role in energy production, have emerged as multifunctional organelles at the intersection of bioenergetics, metabolic signaling, and immunity. However, the understanding of their exact contributions to immunity and inflammation is still developing. This review first introduces the innovative concept of intracellular immunity, emphasizing how mitochondria serve as critical immune signaling hubs. They are instrumental in recognizing and responding to pathogen and danger signals, and in modulating immune responses. We also propose mitochondria as the leading immune organelles, drawing parallels with the broader immune system in their functions of antigen presentation, immune regulation, and immune response. Our comprehensive review explores mitochondrial immune signaling pathways, their therapeutic potential in managing inflammation and chronic diseases, and discusses cutting-edge methodologies for mitochondrial research. Targeting a broad readership of both experts in mitochondrial functions and newcomers to the field, this review sets forth new directions that could transform our understanding of intracellular immunity and the integrated immune functions of intracellular organelles.

Keywords:  Immune responses; Immunometabolism; Inflammation; Intracellular immunity; Organelle crosstalk; mitochondria

DOI:  https://doi.org/10.1016/j.redox.2024.103331
Ecotoxicol Environ Saf. 2024 Aug 31. pii: S0147-6513(24)01028-5. [Epub ahead of print]283 116952

Glycolytic reprogramming governs crystalline silica-induced pyroptosis and inflammation through promoting lactylation modification.

Xiaojie You, Yujia Xie, Qiyou Tan, Chao Zhou, Pei Gu, Yingdie Zhang, Shiyu Yang, Haoyu Yin, Bingxin Shang, Yuxin Yao, Dongming Wang, Jixuan Ma, Weihong Chen, Xiaoju Zhang.

  Prolonged inhalation of environmental crystalline silica (CS) can cause silicosis, characterized by persistent pulmonary inflammation and irreversible fibrosis, but the mechanism has not been elucidated. To uncover the role and underlying mechanism of glycolytic reprogramming in CS-induced pulmonary inflammation, the mouse silicosis models and glycolysis inhibition models were established in vivo. And the CS-induced macrophage activation models were utilized to further explore the underlying mechanism in vitro. The results showed that CS induced lung inflammation accompanied by glycolytic reprogramming and pyroptosis. The application of glycolysis inhibitor (2-DG) suppressed CS-induced pyroptosis and alleviated lung inflammation. In vitro, 2-DG effectively impeded CS-induced macrophage pyroptosis and inflammatory response. Mechanistically, 2-DG suppressed pyroptosis by inhibiting NLRP3 inflammasome activation both in vivo and in vitro. Furtherly, metabolite lactate facilitated NLRP3-dependent pyroptosis synergistically with CS particles, while blocking the source of lactate largely alleviated NLRP3 inflammasome activation and subsequent pyroptosis triggered by CS. More profoundly, the increment of lactate induced by CS might drive NLRP3-dependent pyroptosis by increasing histone lactylation levels. In conclusion, our findings demonstrated inhibiting glycolytic reprogramming could alleviate CS-induced inflammatory response through suppressing NLRP3 -dependent pyroptosis. Increased glycolytic metabolite lactate and protein lactylation modifications might represent significant mechanisms during CS-induced NLRP3 activation and macrophage pyroptosis.

Keywords:  Crystalline silica; Glycolytic reprogramming; Lactate; Lactylation; Lung inflammation; Pyroptosis

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116952
bioRxiv. 2024 Aug 21. pii: 2024.08.20.608809. [Epub ahead of print]

Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity.

Yem J Alharithi, Elysse A Phillips, Tim D Wilson, Sneha P Couvillion, Carrie D Nicora, Priscila Darakjian, Shauna Rakshe, Suzanne S Fei, Brittany Counts, Thomas O Metz, Robert Searles, Sushil Kumar, Alina Maloyan.

Maternal obesity puts the offspring at high risk of developing obesity and cardio-metabolic diseases in adulthood. Here, using a mouse model of maternal high-fat diet (HFD)-induced obesity, we show that whole body fat content of the offspring of HFD-fed mothers (Off-HFD) increases significantly from very early age when compared to the offspring regular diet-fed mothers (Off-RD). We have previously shown significant metabolic and immune perturbations in the bone marrow of newly-weaned offspring of obese mothers. Therefore, we hypothesized that lipid metabolism is altered in the bone marrow Off-HFD in newly-weaned offspring of obese mothers when compared to the Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from three-week-old offspring of regular and high fat diet-fed mothers. Diacylgycerols (DAGs), triacylglycerols (TAGs), sphingolipids and phospholipids, including plasmalogen, and lysophospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in offspring of obese mothers, suggesting reduced delivery of cholesterol to bone marrow cells. This was accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from three-week-old mice and conducted metabolomics, lipidomics, and transcriptomics analyses. The lipidomic profiles of these bone marrow myeloid cells were largely similar to that seen in bone marrow cells and included increases in DAGs and phospholipids alongside decreased TAGs, except for long-chain TAGs, which were significantly increased. Our data also revealed significant sex-dependent changes in amino acids and metabolites related to energy metabolism. Transcriptomic analysis revealed altered expression of genes related to major immune pathways including macrophage alternative activation, B-cell receptor signaling, TGFβ signaling, and communication between the innate and adaptive immune systems. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly-weaned offspring of obese mothers, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.

DOI: https://doi.org/10.1101/2024.08.20.608809
mBio. 2024 Aug 29. e0305723

The role of lipids in regulating macrophage antifungal immunity.

Sophie Rouvray, Rebecca A Drummond.

  Macrophages are critical components of the antifungal immune response. Disturbance in the number or function of these innate immune cells can significantly increase susceptibility to invasive fungal infections. Pathogenic fungi cause billions of infections every year and have an unmet clinical need, with many infections associated with unacceptably high mortality rates that primarily affect vulnerable patients with underlying immune defects. Lipid metabolism has been increasingly appreciated to significantly influence macrophage function, particularly of macrophages residing in lipid-rich organs, such as the brain, or macrophages specialized at clearing dead cells including alveolar macrophages in the lungs. In this review, we provide an overview of macrophage lipid metabolism, and discuss how lipid recycling and dysregulation affect key macrophage functions relevant for antifungal immunity including phagocytosis, functional polarization, and inflammasome activation. We focus on the fungal pathogen Cryptococcus neoformans, as this is the most common cause of death from fungal infection in humans and because several lines of evidence have already linked lipid metabolism in the regulation of C. neoformans and macrophage interactions.

Keywords:  Cryptococcus neoformans; cholesterol; macrophages; meningitis

DOI:  https://doi.org/10.1128/mbio.03057-23
bioRxiv. 2024 Aug 19. pii: 2024.08.18.607992. [Epub ahead of print]

The glycolytic reaction PGAM unexpectedly restrains Th17 pathogenicity and Th17-dependent autoimmunity.

Chao Wang, Allon Wagner, Johannes Fessler, David DeTomaso, Sarah Zaghouani, Yulin Zhou, Kerry Pierce, Raymond A Sobel, Clary Clish, Nir Yosef, Vijay K Kuchroo.

Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate the relevance of individual glycolytic reactions in determining the pathogenicity of T helper 17 (Th17) cells using single-cell RNA-seq and Compass, an algorithm we previously developed for estimating metabolic flux from single-cell transcriptomes. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in these cells, whereas both its upstream and downstream reactions were positively correlated. Perturbation of phosphoglycerate mutase (PGAM), an enzyme required for 3PG to 2PG conversion, resulted in an increase in protein expression of IL2, IL17, and TNFa, as well as induction of a pathogenic gene expression program. Consistent with PGAM playing a pro-regulatory role, inhibiting PGAM in Th17 cells resulted in exacerbated autoimmune responses in the adoptive transfer model of experimental autoimmune encephalomyelitis (EAE). Finally, we further investigated the effects of modulating glucose concentration on Th17 cells in culture. Th17 cells differentiated under high- and low-glucose conditions substantially differed in their metabolic and effector transcriptomic programs, both central to Th17 function. Importantly, the PGAM-dependent gene module marks the least pathogenic state of Th17 cells irrespective of glucose concentration. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of Th17 pathogenicity.

DOI: https://doi.org/10.1101/2024.08.18.607992
medRxiv. 2024 Aug 08. pii: 2024.08.08.24311598. [Epub ahead of print]

A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD.

Lina Welz, Danielle Mm Harris, Na-Mi Kim, Abrar I Alsaadi, Qicong Wu, Mhmd Oumari, Jan Taubenheim, Valery Volk, Graziella Credido, Eric Koncina, Pranab K Mukherjee, Florian Tran, Laura Katharina Sievers, Polychronis Pavlidis, Nick Powell, Florian Rieder, Elisabeth Letellier, Silvio Waschina, Christoph Kaleta, Friedrich Feuerhake, Bram Verstockt, Melanie R McReynolds, Philip Rosenstiel, Stefan Schreiber, Konrad Aden.

Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo nicotinamide adenine dinucleotide (NAD + ) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail, we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a decrease of NAD + . We further demonstrate that Trp degradation along the KP occurs locally in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT in-vitro induces NAD + depletion and a pro-inflammatory state, which can largely be rescued by bypassing QPRT via other NAD + precursors. We hence propose a model of impaired de-novo NAD + synthesis from Trp in IBD. These findings point towards the replenishment of NAD + precursors as a novel therapeutic pathway in IBD.

DOI: https://doi.org/10.1101/2024.08.08.24311598
Cell Biochem Biophys. 2024 Sep 06.

TREM2 Impairs Glycolysis to Interrupt Microglial M1 Polarization and Inflammation via JAK2/STAT3 Axis.

Chanyuan Liu, Xueying Zhou.

  Cerebral ischemia/reperfusion injury (IRI) is a primary pathophysiological basis of ischemic stroke, a dreadful cerebrovascular event carrying substantial disability and lethality. Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane glycoprotein that has been notified as a protective factor for cerebral ischemic stroke. On this basis, the paper is thereby goaled to interpret the probable activity and downstream mechanism of TREM2 against cerebral IRI. Cerebral IRI was simulated in murine microglial BV2 cells under oxygen-glucose deprivation and reperfusion (OGD/R) conditions. Western blotting ascertained the expressions of TREM2 and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis-associated proteins. ELISA and RT-qPCR assayed the secretion of inflammatory cytokines. Immunofluorescence and western blotting estimated macrophage polarization. Glycolysis activation was measured through evaluating lactic acid and extracellular acidification rate (ECAR). RT-qPCR and western blotting examined the expressions of glycolytic genes. TREM2 was abnormally expressed and JAK2/STAT3 axis was aberrantly activated in BV2 cells in response to OGD/R. Elevation of TREM2 repressed the inflammatory reaction and glycolysis, inhibited the JAK2/STAT3 axis, whereas promoted M1-to-M2 polarization in OGD/R-injured BV2 cells. Upregulated TREM2 inactivated the glycolytic pathway to relieve OGD/R-induced inflammatory injury and M1 macrophage polarization. Besides, STAT3 activator, colivelin, aggravated the glycolysis, inflammatory injury and drove M1-like macrophage polarization in TREM2-overexpressing BV2 cells exposed to OGD/R. Collectively, TREM2 might produce anti-inflammatory potential in cerebral IRI, which might dependent on the inactivation of glycolytic pathway via intermediating the JAK2/STAT3 axis.

Keywords:  Glycolysis; JAK2/STAT3 axis; M1/M2 polarization; Microglia; OGD/R; TREM2

DOI:  https://doi.org/10.1007/s12013-024-01520-5
Theranostics. 2024 ;14(12): 4874-4893

Engaging natural regulatory myeloid cells to restrict T-cell hyperactivation-induced liver inflammation via extracellular vesicle-mediated purine metabolism regulation.

Fan Yang, Ruoting Men, Linling Lv, Leyu Zhou, Qiaoyu Deng, Xianglin Wang, Jingping Liu, Li Yang.

  Rationale: Dysregulated T-cell immune response-mediated inflammation plays critical roles in the pathology of diverse liver diseases, but the underlying mechanism of liver immune homeostasis control and the specific therapies for limiting T-cell overactivation remain unclear. Methods: The metabolic changes in concanavalin A (ConA) mice and autoimmune hepatitis (AIH) patients and their associations with liver injury were analyzed. The expression of purine catabolism nucleases (e.g., CD39 and CD73) on liver cells and immune cells was assessed. The effects of MCregs and their extracellular vesicles (EVs) on CD4+ T-cell overactivation and the underlying mechanism were also explored. Results: Our findings revealed significant alterations in purine metabolism in ConA mice and AIH patients, which correlated with liver injury severity and therapeutic response. CD39 and CD73 were markedly upregulated on CD11b+Gr-1+ MCs under liver injury conditions. The naturally expanded CD39+CD73+Gr-1highCD11b+ MCreg subset during early liver injury effectively suppressed CD4+ T-cell hyperactivation and liver injury both in vitro and in vivo. Mechanistically, MCregs released CD73high EVs, which converted extracellular AMP to immunosuppressive metabolites (e.g., adenosine and inosine), activating the cAMP pathway and inhibiting glycolysis and cytokine secretion in activated CD4+ T cells. Conclusions: This study provides insights into the mechanism controlling immune homeostasis during the early liver injury phase and highlights that MCreg or MCreg-EV therapy may be a specific strategy for preventing diverse liver diseases induced by T-cell overactivation.

Keywords:  T cells; extracellular vesicles; liver inflammation; purine metabolism; regulatory myeloid cells

DOI:  https://doi.org/10.7150/thno.97427
Antioxid Redox Signal. 2024 Sep 03.

Succinate activates UCP2 to suppress neuroinflammation and confer protection following intracerebral hemorrhage.

Yecheng Wang, Caiyun Huang, Xiaoying Wang, Rong Cheng, Xue Li, Jiahao Wang, Lu Zhang, Fuhao Li, Hao Wang, Xinyu Li, Yi Li, Yiqing Xia, Jian Cheng, Xiaofan Pan, Jia Jia, Guo-Dong Xiao.

AIMS: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models.
RESULTS: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH.
INNOVATION AND CONCLUSION: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate.
KEY WORDS: succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage.

DOI: https://doi.org/10.1089/ars.2024.0573
Int J Mol Sci. 2024 Aug 20. pii: 9029. [Epub ahead of print]25(16):

Effects of Fasting on THP1 Macrophage Metabolism and Inflammatory Profile.

Julia Rius-Bonet, Salvador Macip, Marta Massip-Salcedo, Daniel Closa.

  Fasting can affect the body's inflammatory response, and this has been linked to potential health benefits, including improvements for people with rheumatic diseases. In this work, we evaluated, in vitro, how changes in nutrient availability alter the inflammatory response of macrophages. Macrophage-differentiated THP1 cells were cultured, deprived of FCS or subjected to cycles of FCS deprivation and restoration to mimic intermittent fasting. Changes in the macrophage phenotype, the cells' response to inflammatory stimuli and the level of mitochondrial alteration were assessed. The results indicate that while periods of serum starvation are associated with a decrease in IL1β and TNFα expression, consistent with an anti-inflammatory response, intermittent serum starvation cycles promote a pro-inflammatory phenotype. Rapid changes in reducing capacity and mitochondrial response were also observed. Of note, while some changes, such as the production of oxygen free radicals, were reversed with refeeding, others, such as a decrease in reducing capacity, were maintained and even increased. This study shows that different fasting protocols can have diverging effects and highlights that time-limited nutrient changes can significantly affect macrophage functions in cell cultures. These findings help elucidate some of the mechanisms by which specific fasting dietary interventions could help control inflammatory diseases.

Keywords:  fasting; inflammation; intermittent fasting; macrophages; rheumatic diseases

DOI:  https://doi.org/10.3390/ijms25169029
bioRxiv. 2024 Aug 07. pii: 2023.01.26.525718. [Epub ahead of print]

Helminth-derived metabolites induce tolerogenic functional, metabolic, and transcriptional signatures in dendritic cells that attenuate experimental colitis.

Nathalia L Malacco, Aubrey N Michi, Elizabeth Siciliani, Ana G Madrigal, Tamara Sternlieb, Ghislaine Fontes, Irah L King, Igor Cestari, Armando Jardim, Mary M Stevenson, Fernando Lopes.

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases in which abdominal pain, bloody diarrhea, weight loss, and fatigue collectively result in diminished quality of patient life. The disappearance of intestinal helminth infections in Western societies is associated with an increased prevalence of IBD and other immune-mediated inflammatory diseases. Evidence indicates that helminths induce tolerogenic dendritic cells (tolDCs), which promote intestinal tolerance and attenuate intestinal inflammation characteristic of IBD, but the exact mechanism is unclear. Helminth-derived excretory-secretory (HES) products including macromolecules, proteins, and polysaccharides have been shown to modulate the antigen presenting function of DCs with down-stream effects on effector CD4 + T cells. Previous studies indicate that DCs in helminth-infected animals induce tolerance to unrelated antigens and DCs exposed to HES display phenotypic and functional features of tolDCs. Here, we identify that nonpolar metabolites (HnpM) produced by a helminth, the murine gastrointestinal nematode Heligmosomoides polygyrus bakeri (Hpb), induce tolDCs as evidenced by decreased LPS-induced TNF and increased IL-10 secretion and reduced expression of MHC-II, CD86, and CD40. Furthermore, these DCs inhibited OVA-specific CD4 + T cell proliferation and induced CD4 + Foxp3 + regulatory T cells. Adoptive transfer of HnpM-induced tolDCs attenuated DSS-induced intestinal inflammation characteristic of IBD. Mechanistically, HnpM induced metabolic and transcriptional signatures in BMDCs consistent with tolDCs. Collectively, our findings provide groundwork for further investigation into novel mechanisms regulating DC tolerance and the role of helminth secreted metabolites in attenuating intestinal inflammation associated with IBD. Summary Sentence: Metabolites produced by Heligmosomoides polygyrus induce metabolic and transcriptional changes in DCs consistent with tolDCs, and adoptive transfer of these DCs attenuated DSS-induced intestinal inflammation.

DOI: https://doi.org/10.1101/2023.01.26.525718
J Nanobiotechnology. 2024 Aug 29. 22(1): 517

GAPDH-Silence Microsphere via Reprogramming Macrophage Metabolism and eradicating Bacteria for Diabetic infection bone regeneration.

Jiale Jin, Xiaowei Xia, Chengxin Ruan, Zhiyuan Luo, Yiqi Yang, Dongyu Wang, Yifang Qin, Dongdong Li, Yong Zhang, Yihe Hu, Pengfei Lei.

  Macrophage metabolism dysregulation, which is exacerbated by persistent stimulation in infectious and inflammatory diseases, such as diabetic infectious bone defects (DIBD), eventually leads to the failure of bone repair. Here, we have developed an injectable, macrophage-modulated GAPDH-Silence drug delivery system. This microsphere comprises chondroitin sulfate methacrylate (CM) and methacrylated gelatin (GM), while the dimethyl fumarate (DMF)-loaded liposome (D-lip) is encapsulated within the microsphere (CM@GM), named D-lip/CM@GM. Triggered by the over-expressed collagenase in DIBD, the microspheres degrade and release the encapsulated D-lip. D-lip could modulate metabolism by inhibiting GAPDH, which suppresses the over-activation of glycolysis, thus preventing the inflammatory response of macrophages in vitro. While beneficial for macrophages, D-lip/CM@GM is harmful to bacteria. GAPDH, while crucial for glycolysis of staphylococcal species (S. aureus), can be effectively countered by D-lip/CM@GM. We are utilizing existing drugs in innovative ways to target central metabolism for effective eradication of bacteria. In the DIBD model, our results confirmed that the D-lip/CM@GM enhanced bacteria clearance and reprogrammed dysregulated metabolism, thereby significantly improving bone regeneration. In conclusion, this GAPDH-Silence microsphere system may provide a viable strategy to promote diabetic infection bone regeneration.

Keywords:  Diabetic infection bone defect; Dimethyl fumarate; Macrophage metabolism; Microsphere

DOI:  https://doi.org/10.1186/s12951-024-02787-9
J Virol. 2024 Aug 30. e0104824

Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.

Yuan Zhao, Chan Ding, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Herman W Favoreel, Xiangdong Li.

  Pseudorabies virus (PRV) utilizes multiple strategies to inhibit type I interferon (IFN-I) production and signaling to achieve innate immune evasion. Among several other functions, mitochondria serve as a crucial immune hub in the initiation of innate antiviral responses. It is currently unknown whether PRV inhibits innate immune responses by manipulating mitochondria. In this study, we found that PRV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. In addition, PRV infection triggered PINK1-Parkin-mediated mitophagy to eliminate the impaired mitochondria, which resulted in a suppression of IFN-I production, thereby promoting viral replication. Furthermore, we found that mitophagy resulted in the degradation of the mitochondrial antiviral signaling protein, which is located on the mitochondrial outer membrane. In conclusion, the data of the current study indicate that PRV-induced mitophagy represents a previously uncharacterized PRV evasion mechanism of the IFN-I response, thereby promoting virus replication.IMPORTANCEPseudorabies virus (PRV), a pathogen that induces different disease symptoms and is often fatal in domestic animals and wildlife, has caused great economic losses to the swine industry. Since 2011, different PRV variant strains have emerged in Asia, against which current commercial vaccines may not always provide optimal protection in pigs. In addition, there are indications that some of these PRV variant strains may sporadically infect people. In the current study, we found that PRV infection causes mitochondria injury. This is associated with the induction of mitophagy to eliminate the damaged mitochondria, which results in suppressed antiviral interferon production and signaling. Hence, our study reveals a novel mechanism that is used by PRV to antagonize the antiviral host immune response, providing a theoretical basis that may contribute to the research toward and development of new vaccines and antiviral drugs.

Keywords:  MAVS; interferons production inhibition; mitochondria; mitophagy; pseudorabies virus (PRV)

DOI:  https://doi.org/10.1128/jvi.01048-24
J Leukoc Biol. 2024 Aug 30. pii: qiae171. [Epub ahead of print]

Obesity alters the macrophages' response to Leishmania major in C57BL/6 mice.

Vinicius Dantas Martins, Leonardo Vaz, Sara Candida Barbosa, Pierre Henrique de Menezes Paixão, Licia Torres, Marcos Felipe Andrade de Oliveira, Mariana de Almeida Oliveira, Leda Quercia Vieira, Ana Maria Caetano de Faria, Tatiani Uceli Maioli.

  Obesity is a global pandemic associated with several comorbidities, such as cardiovascular diseases and type 2 diabetes. It is also a predisposing factor for infectious diseases, increasing mortality rates. Moreover, diet-induced obesity can cause metabolic fluctuations that affect macrophage differentiation in various organs. In this sense, we investigated how bone marrow-derived macrophages and tissue-resident macrophages in the skin, which have been differentiated in a host with metabolic syndrome and with previous inflammatory burden, respond to Leishmania major infection. Our findings suggest that bone marrow-derived macrophages from obese C57BL/6 mice, even when cultivated in vitro with inflammatory stimuli, are more susceptible to L. major. These macrophages produce less tumor necrosing factor (TNF) and nitric oxide (NO) and show higher arginase activity. Furthermore, obese mice infected with an intermediate dose of L. major in the skin had more severe lesions when analyzed for ulceration, diameter, thickness, and parasite burden. The increase in lesion severity in obese mice was associated with a higher frequency of tissue-resident macrophages, which are less efficient in killing parasites. We also used CCR2-/- mice, which predominantly have tissue-resident macrophages, and found that lesion resolution was delayed in association with CCR2 deficiency. Additionally, obesity potentiated tissue damage, resulting in higher frequency of tissue-resident macrophages. Our results demonstrate that obesity can alter macrophage responses to infection, leading to increased susceptibility to L. major and more severe cutaneous leishmaniasis. These findings may have important implications for managing obesity-related infections and the development of new therapies for cutaneous leishmaniasis.

Keywords:  leishmania infection; macrophages; obesity

DOI:  https://doi.org/10.1093/jleuko/qiae171
bioRxiv. 2024 Jul 31. pii: 2023.09.06.556606. [Epub ahead of print]

Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.

Preeti Yadav, Javier Gómez Ortega, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper Wang, Tatsuya Tsukui, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L Eckalbar, Ari B Molofsky, Paul J Wolters, Stanley J Tamaki, Trever Bivona, Adam R Abate, Allon Wagner, Kevin M Tharp, Mallar Bhattacharya.

Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.

DOI: https://doi.org/10.1101/2023.09.06.556606
Nature. 2024 Sep 04.

Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming.

Jean-Rémi Lavillegrand, Rida Al-Rifai, Sara Thietart, Théo Guyon, Marie Vandestienne, Raphael Cohen, Vincent Duval, Xiaodan Zhong, Daniel Yen, Mumin Ozturk, Yutaka Negishi, Joanne Konkel, Emmanuel Pinteaux, Olivia Lenoir, Jose Vilar, Ludivine Laurans, Bruno Esposito, Marius Bredon, Harry Sokol, Marc Diedisheim, Antoine-Emmanuel Saliba, Alma Zernecke, Clément Cochain, Jessica Haub, Alain Tedgui, Nancy A Speck, Soraya Taleb, Musa M Mhlanga, Andreas Schlitzer, Niels P Riksen, Hafid Ait-Oufella.

Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications1. However, individuals often change their dietary habits over time2, and the effects of an alternating high-fat diet (HFD) on atherosclerosis remain unclear. Here, to address this relevant issue, we developed a protocol using atherosclerosis-prone mice to compare an alternating versus continuous HFD while maintaining similar overall exposure periods. We found that an alternating HFD accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared with a continuous HFD. This pro-atherogenic effect of the alternating HFD was also observed in Apoe-/-Rag2-/- mice lacking T, B and natural killer T cells, ruling out the role of the adaptive immune system in the observed phenotype. Discontinuing the HFD in the alternating HFD group downregulated RUNX13, promoting inflammatory signalling in bone marrow myeloid progenitors. After re-exposure to an HFD, these cells produced IL-1β, leading to emergency myelopoiesis and increased neutrophil levels in blood. Neutrophils infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis. Specific depletion of neutrophils or inhibition of IL-1β pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1β-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD.

DOI: https://doi.org/10.1038/s41586-024-07693-6
Cell Rep. 2024 Aug 30. pii: S2211-1247(24)01037-4. [Epub ahead of print]43(9): 114686

H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response.

Ruijie Wang, Chuwen Li, Zhongyi Cheng, Mingyu Li, Jianbo Shi, Zhiyuan Zhang, Shufang Jin, Hailong Ma.

  Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8+ T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8+ T cell exhaustion, and cholesterol-modified siIL11 restores CD8+ T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.

Keywords:  CP: Cancer; CP: Metabolism; T cell dysfunction; head and neck squamous cell carcinoma; histone lactylation; interleukin-11; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.114686