bims-imicid 2024-08-25 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–08–25
25 papers selected by
Dylan Ryan, University of Cambridge

PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.
Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.
Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation.
Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection.
Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.
Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.
Divergent effects of itaconate isomers on Coxiella burnetii growth in macrophages and in axenic culture.
Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.
Hypoxia-inducible factor-1α promotes macrophage functional activities in protecting hypoxia-tolerant large yellow croaker (Larimichthys crocea) against Aeromonas hydrophila infection.
The L-lactate dehydrogenases of Pseudomonas aeruginosa are conditionally regulated but both contribute to survival during macrophage infection.
Unraveling the immunometabolism puzzle: Deciphering systemic sclerosis pathogenesis.
Inflammatory stimulus-responsive polymersomes reprogramming glucose metabolism mitigates rheumatoid arthritis.
CD36 restricts lipid-associated macrophages accumulation in white adipose tissues during atherogenesis.
Advances in the mechanism of action of short-chain fatty acids in psoriasis.
Fueling Alzheimer's Disease: Where Does Immunometabolism Stand?
The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.
Inherent preference for polyunsaturated fatty acids instigates ferroptosis of Treg cells that aggravates high-fat-diet-related colitis.
Alzheimer's and metabolism wed with IDO1.
Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment.
Leukemia inhibitory factor drives transcriptional programs that promote lipid accumulation and M2 polarization in macrophages.
Targeting PDHK1 by DCA to restore NK cell function in hepatocellular carcinoma.
S-adenosyl-L-methionine supplementation alleviates aortic dissection by decreasing inflammatory infiltration.
Metabolic profiling of psoriasis vulgaris and palmoplantar pustulosis.

Sci Immunol. 2024 Aug 23. 9(98): eadn2717

PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.

Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho.

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.

DOI: https://doi.org/10.1126/sciimmunol.adn2717
Mol Cell. 2024 Aug 06. pii: S1097-2765(24)00619-1. [Epub ahead of print]

Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.

Zhenxi Zhang, Yanting Yang, Yang Chen, Jingyu Su, Wenjing Du.

  The functional integrity of CD8+ T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8+ T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8+ T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8+ T cell activation and anti-tumor immune response in vitro and in vivo. Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8+ T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8+ T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.

Keywords:  CD8(+) T cell; DAPK1; antitumor immunity; fumarate; malic enzyme 2; metabolite sensing

DOI:  https://doi.org/10.1016/j.molcel.2024.07.021
Inflamm Res. 2024 Aug 21.

Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.

Lewis Yu, Nancy Wu, Okmi Choi, Khoa Dinh Nguyen.

   BACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.
METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.
RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45hi infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45low microglia and F4/80 + CD45hi infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.
CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.

Keywords:  Amyotrophic lateral sclerosis; Immunometabolism; Inflammation; Innate immunity

DOI:  https://doi.org/10.1007/s00011-024-01935-z
Nat Commun. 2024 Aug 22. 15(1): 7241

Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation.

Kuei-Pin Chung, Chih-Ning Cheng, Yi-Jung Chen, Chia-Lang Hsu, Yen-Lin Huang, Min-Shu Hsieh, Han-Chun Kuo, Ya-Ting Lin, Yi-Hsiu Juan, Kiichi Nakahira, Yen-Fu Chen, Wei-Lun Liu, Sheng-Yuan Ruan, Jung-Yien Chien, Maria Plataki, Suzanne M Cloonan, Peter Carmeliet, Augustine M K Choi, Ching-Hua Kuo, Chong-Jen Yu.

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

DOI: https://doi.org/10.1038/s41467-024-51683-1
Cell Rep. 2024 Aug 18. pii: S2211-1247(24)00982-3. [Epub ahead of print]43(8): 114632

Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies.

  Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.

Keywords:  CP: Cancer; CP: Metabolism; GLS1; LDHA; Tpex

DOI:  https://doi.org/10.1016/j.celrep.2024.114632
FEBS Lett. 2024 Aug 18.

The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection.

Soumya Mal, Debayan Majumder, Pankaj Birari, Arun Kumar Sharma, Umesh Gupta, Kuladip Jana, Manikuntala Kundu, Joyoti Basu.

  Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb-triggered regulation of the innate immune response. Mtb infection downregulated microRNA-26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF-1α-dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF-1α, as well as the release of interleukin (IL)-1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL-6 but augmented anti-inflammatory arginase expression. The miR-26a/SIRT6/HIF-1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response.

Keywords:  Mycobacterium tuberculosis; glycolysis; immunometabolism; innate immunity; macrophage response; sirtuin 6

DOI:  https://doi.org/10.1002/1873-3468.15001
Cell Rep. 2024 Aug 20. pii: S2211-1247(24)00999-9. [Epub ahead of print]43(9): 114648

Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.

Jingjing Tang, Xiao Wang, Shukun Chen, Tianyuan Chang, Yanchao Gu, Fuhua Zhang, Jing Hou, Yi Luo, Mengyuan Li, Jianan Huang, Mohua Liu, Lei Zhang, Yao Wang, Xihui Shen, Lei Xu.

  Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD+/NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD+/NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD+/NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD+/NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD+/NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD+/NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.

Keywords:  CP: Immunology; CP: Metabolism; IFN; LPS; NAD(+)/NADH ratio; Salmonella Typhimurium; immunometabolites; lipopolysaccharide; metabolic reprogramming; proinflammatory responses; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2024.114648
Nat Commun. 2024 Aug 21. 15(1): 7173

Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.

Laurent L'homme, Benan Pelin Sermikli, Joel T Haas, Sébastien Fleury, Sandrine Quemener, Valentine Guinot, Emelie Barreby, Nathalie Esser, Robert Caiazzo, Hélène Verkindt, Benjamin Legendre, Violeta Raverdy, Lydie Cheval, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels, Myriam Aouadi, François Pattou, Bart Staels, David Dombrowicz.

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

DOI: https://doi.org/10.1038/s41467-024-51078-2
Front Immunol. 2024 ;15 1427457

Divergent effects of itaconate isomers on Coxiella burnetii growth in macrophages and in axenic culture.

Md Nur A Alam Siddique, Fabian Kellermeier, Martha Ölke, Mingming Zhao, Konrad Büssow, Peter J Oefner, Anja Lührmann, Katja Dettmer, Roland Lang.

  Aconitate decarboxylase-1 (ACOD1) is expressed by activated macrophages and generates itaconate that exerts anti-microbial and immunoregulatory effects. ACOD1-itaconate is essential for macrophage-mediated control of the intracellular pathogen Coxiella (C.) burnetii, which causes Q fever. Two isomers of itaconate, mesaconate and citraconate, have overlapping yet distinct activity on macrophage metabolism and inflammatory gene expression. Here, we found that all three isomers inhibited the growth of C. burnetii in axenic culture in ACCM-2 medium. However, only itaconate reduced C. burnetii replication efficiently in Acod1-/- macrophages. In contrast, addition of citraconate strongly increased C. burnetii replication in Acod1+/- macrophages, whereas mesaconate weakly enhanced bacterial burden in Acod1-/- macrophages. Analysis of intracellular isomers showed that exogenous citraconate and mesaconate inhibited the generation of itaconate by infected Acod1+/- macrophages. Uptake of added isomers into Acod1-/- macrophages was increased after infection for itaconate and mesaconate, but not for citraconate. Mesaconate, but not citraconate, competed with itaconate for uptake into macrophages. Taken together, inhibition of itaconate generation by macrophages and interference with the uptake of extracellular itaconate could be identified as potential mechanisms behind the divergent effects of citraconate and mesaconate on C. burnetii replication in macrophages or in axenic culture.

Keywords:  ACOD1; IRG1; citraconate; infection; itaconate; mesaconate; transport; uptake

DOI:  https://doi.org/10.3389/fimmu.2024.1427457
PLoS Biol. 2024 Aug 23. 22(8): e3002781

Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

Bjarke Haldrup Pedersen, Filipa Bica Simões, Ivan Pogrebnyakov, Martin Welch, Helle Krogh Johansen, Søren Molin, Ruggero La Rosa.

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a convergent shift in metabolic function(s) linked with the persistence phenotype during Pseudomonas aeruginosa colonization in the airways of people with cystic fibrosis. We show that clinically relevant mutations in the key metabolic enzyme, pyruvate dehydrogenase, lead to a host-specialized metabolism together with a lower virulence and immune response recruitment. These changes in infection phenotype are mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate, respectively. Our results show how metabolic adaptations directly impinge on persistence and pathogenicity in this organism.

DOI: https://doi.org/10.1371/journal.pbio.3002781
Front Immunol. 2024 ;15 1410082

Hypoxia-inducible factor-1α promotes macrophage functional activities in protecting hypoxia-tolerant large yellow croaker (Larimichthys crocea) against Aeromonas hydrophila infection.

Yibo Zhang, Xuelei Wang, Zhenyu Gao, XuJie Li, Ran Meng, Xiongfei Wu, Jie Ding, Weiliang Shen, Junquan Zhu.

  The immune system requires a high energy expenditure to resist pathogen invasion. Macrophages undergo metabolic reprogramming to meet these energy requirements and immunologic activity and polarize to M1-type macrophages. Understanding the metabolic pathway switching in large yellow croaker (Larimichthys crocea) macrophages in response to lipopolysaccharide (LPS) stimulation and whether this switching affects immunity is helpful in explaining the stronger immunity of hypoxia-tolerant L. crocea. In this study, transcript levels of glycolytic pathway genes (Glut1 and Pdk1), mRNA levels or enzyme activities of glycolytic enzymes [hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), and lactate dehydrogenase A (LDHA)], aerobic respiratory enzymes [pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and succinate dehydrogenase (SDH)], metabolites [lactic acid (LA) and adenosine triphosphate (ATP)], levels of bactericidal products [reactive oxygen species (ROS) and nitric oxide (NO)], and transcripts and level changes of inflammatory factors [IL1β, TNFα, and interferon (IFN) γ] were detected in LPS-stimulated L. crocea head kidney macrophages. We showed that glycolysis was significantly induced, the tricarboxylic acid (TCA) cycle was inhibited, and metabolic reprogramming occurred, showing the Warburg effect when immune cells were activated. To determine the potential regulatory mechanism behind these changes, LcHIF-1α was detected and found to be significantly induced and transferred to the nucleus after LPS stimulation. LcHif-1α interference led to a significant reduction in glycolytic pathway gene transcript expression, enzyme activity, metabolites, bactericidal substances, and inflammatory factor levels; a significant increase in the aerobic respiration enzymes; and decreased migration, invasion, and phagocytosis. Further ultrastructural observation by electron microscopy showed that fewer microspheres contained phagocytes and that more cells were damaged after LcHif-1α interference. LcHif-1α overexpression L. crocea head kidney macrophages showed the opposite trend, and promoter activities of Ldha and Il1β were significantly enhanced after LcHif-1α overexpression in HEK293T cells. Our data showed that LcHIF-1α acted as a metabolic switch in L. crocea macrophages and was important in polarization. Hypoxia-tolerant L. crocea head kidney showed a stronger Warburg effect and inhibited the TCA cycle, higher metabolites, and bactericidal substance levels. These results collectively revealed that LcHif-1α may promote the functional activities of head kidney macrophages in protecting hypoxia-tolerant L. crocea from Aeromonas hydrophila infection.

Keywords:  Larimichthys crocea; glycolysis; immunity; macrophages; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2024.1410082
mBio. 2024 Aug 20. e0085224

The L-lactate dehydrogenases of Pseudomonas aeruginosa are conditionally regulated but both contribute to survival during macrophage infection.

Lindsey C Florek, Xi Lin, Yu-Cheng Lin, Min-Han Lin, Arijit Chakraborty, Alexa Price-Whelan, Liang Tong, Laurence Rahme, Lars E P Dietrich.

  Pseudomonas aeruginosa is an opportunistic pathogen that thrives in environments associated with human activity, including soil and water altered by agriculture or pollution. Because L-lactate is a significant product of plant and animal metabolism, it can serve as a carbon source for P. aeruginosa in the diverse settings that it inhabits. In this study, we evaluate the production and use of two redundant P. aeruginosa L-lactate dehydrogenases, termed LldD and LldA. We confirm that the protein LldR represses lldD and identify a new transcription factor, called LldS, that activates lldA; these distinct regulators and the genomic contexts of lldD and lldA contribute to their differential expression. We demonstrate that the lldD and lldA genes are conditionally controlled in response to lactate isomers as well as to glycolate and ɑ-hydroxybutyrate, which, like lactate, are ɑ-hydroxycarboxylates. We also show that lldA is induced when iron availability is low. Our examination of lldD and lldA expression across depth in biofilms indicates a complex pattern that is consistent with the effects of glycolate production, iron availability, and cross-regulation on enzyme preference. Finally, macrophage infection assays reveal that both lldD and lldA contribute to persistence within host cells, underscoring the potential role of L-lactate as a carbon source during P. aeruginosa-eukaryote interactions. Together, these findings help us understand the metabolism of a key resource that may promote P. aeruginosa's success as a resident of contaminated environments and animal hosts.IMPORTANCEPseudomonas aeruginosa is a major cause of lung infections in people with cystic fibrosis, of hospital-acquired infections, and of wound infections. It consumes L-lactate, which is found at substantial levels in human blood and tissues. In this study, we investigated the spatial regulation of two redundant enzymes, called LldD and LldA, which enable L-lactate metabolism in P. aeruginosa biofilms. We uncovered mechanisms and identified compounds that control the preference of P. aeruginosa for LldD versus LldA. We also showed that both enzymes contribute to its ability to survive within macrophages, a behavior that is thought to augment the chronicity and recalcitrance of infections. Our findings shed light on a key metabolic strategy used by P. aeruginosa and have the potential to inform the development of therapies targeting bacterial metabolism during infection.

Keywords:  Pseudomonas aeruginosa; biofilm; glycolate; lactate; macrophages

DOI:  https://doi.org/10.1128/mbio.00852-24
Heliyon. 2024 Aug 15. 10(15): e35445

Unraveling the immunometabolism puzzle: Deciphering systemic sclerosis pathogenesis.

Maryam Masoumi, Ali Bayat Bodaghi, Hossein Khorramdelazad, Erfan Ebadi, Sheyda Houshmandfar, Ali Saeedi-Boroujeni, Jafar Karami.

  The article delves into the pathogenesis of systemic sclerosis (SSc) with an emphasis on immunometabolism dysfunctions. SSc is a complex autoimmune connective tissue disorder with skin and organ fibrosis manifestation, vasculopathy, and immune dysregulation. A growing amount of research indicates that immunometabolism plays a significant role in the pathogenesis of autoimmune diseases, including SSc. The review explores the intricate interplay between immune dysfunction and metabolic alterations, focusing on the metabolism of glucose, lipids, amino acids, the TCA (tricarboxylic acid) cycle, and oxidative stress in SSc disease. According to recent research, there are changes in various metabolic pathways that could trigger or perpetuate the SSc disease. Glycolysis and TCA pathways play a pivotal role in SSc pathogenesis through inducing fibrosis. Dysregulated fatty acid β-oxidation (FAO) and consequent lipid metabolism result in dysregulated extracellular matrix (ECM) breakdown and fibrosis induction. The altered metabolism of amino acids can significantly be involved in SSc pathogenesis through various mechanisms. Reactive oxygen species (ROS) production has a crucial role in tissue damage in SSc patients. Indeed, immunometabolism involvement in SSc is highlighted, which offers potential therapeutic avenues. The article underscores the need for comprehensive studies to unravel the multifaceted mechanisms driving SSc pathogenesis and progression.

Keywords:  Fibrosis; Immunometabolism; Systemic sclerosis; Treatment

DOI:  https://doi.org/10.1016/j.heliyon.2024.e35445
Biomaterials. 2024 Aug 16. pii: S0142-9612(24)00294-1. [Epub ahead of print]312 122760

Inflammatory stimulus-responsive polymersomes reprogramming glucose metabolism mitigates rheumatoid arthritis.

Qin Wang, Jianheng Ren, Xin Lin, Bin Zhang, Jiao Li, Yajun Weng.

  Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Keywords:  Co-delivery; Glycolysis; Inflammation targeting; Polymersomes; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122760
Front Cardiovasc Med. 2024 ;11 1436865

CD36 restricts lipid-associated macrophages accumulation in white adipose tissues during atherogenesis.

Vaya Chen, Jue Zhang, Jackie Chang, Mirza Ahmar Beg, Lance Vick, Dandan Wang, Ankan Gupta, Yaxin Wang, Ziyu Zhang, Wen Dai, Mindy Kim, Shan Song, Duane Pereira, Ze Zheng, Komal Sodhi, Joseph I Shapiro, Roy L Silverstein, Subramaniam Malarkannan, Yiliang Chen.

  Visceral white adipose tissues (WAT) regulate systemic lipid metabolism and inflammation. Dysfunctional WAT drive chronic inflammation and facilitate atherosclerosis. Adipose tissue-associated macrophages (ATM) are the predominant immune cells in WAT, but their heterogeneity and phenotypes are poorly defined during atherogenesis. The scavenger receptor CD36 mediates ATM crosstalk with other adipose tissue cells, driving chronic inflammation. Here, we combined the single-cell RNA sequencing technique with cell metabolic and functional assays on major WAT ATM subpopulations using a diet-induced atherosclerosis mouse model (Apoe-null). We also examined the role of CD36 using Apoe/Cd36 double-null mice. Based on transcriptomics data and differential gene expression analysis, we identified a previously undefined group of ATM displaying low viability and high lipid metabolism and labeled them as "unhealthy macrophages". Their phenotypes suggest a subpopulation of ATM under lipid stress. We also identified lipid-associated macrophages (LAM), which were previously described in obesity. Interestingly, LAM increased 8.4-fold in Apoe/Cd36 double-null mice on an atherogenic diet, but not in Apoe-null mice. The increase in LAM was accompanied by more ATM lipid uptake, reduced adipocyte hypertrophy, and less inflammation. In conclusion, CD36 mediates a delicate balance between lipid metabolism and inflammation in visceral adipose tissues. Under atherogenic conditions, CD36 deficiency reduces inflammation and increases lipid metabolism in WAT by promoting LAM accumulation.

Keywords:  atherosclerosis; inflammation; lipid; macrophage; scRNA-Seq; visceral adipose tissue

DOI:  https://doi.org/10.3389/fcvm.2024.1436865
Int Immunopharmacol. 2024 Aug 18. pii: S1567-5769(24)01449-8. [Epub ahead of print]141 112928

Advances in the mechanism of action of short-chain fatty acids in psoriasis.

Qin Zhang, Linna Zhao, Yu Li, Siyao Wang, Guiling Lu, Hongmei Wang.

  Psoriasis is a prevalent chronic inflammatory and immunological disorder. Its lesions are present as scaly erythema or plaques. Disruptions in the body's immune system play a significant role in developing psoriasis. Recent evidence suggests a potential role of the gut microbiome in autoimmune diseases. Short-chain fatty acids (SCFAs) are the primary metabolites created by gut microbes and play a crucial fuction in autoimmunity. SCFAs act on various cells by mediating signaling to participate in host physiological and pathological processes. These processes encompass body metabolism, maintenance of intestinal barrier function, and immune system modulation. SCFAs can regulate immune cells to enhance the body's immune function, potentially influencing the prevention and treatment of psoriasis. However, the mechanisms underlying the role of SCFAs in psoriasis remain incompletely understood. This paper examines the relationship between SCFAs and psoriasis, elucidating how SCFAs influence the immune system, inflammatory response, and gut barrier in psoriasis. According to the study, in psoriasis, SCFAs have been shown to regulate neutrophils, macrophages, and dendritic cells in the adaptive immune system, as well as T and B cells in the innate immune system. Additionally, we explore the role of SCFAs in psoriasis by maintaining intestinal barrier function, restoring intestinal ecological homeostasis, and investigating the potential therapeutic benefits of SCFAs for psoriasis.

Keywords:  Immunity; Inflammation; Intestinal barrier; Psoriasis; SCFAs

DOI:  https://doi.org/10.1016/j.intimp.2024.112928
J Alzheimers Dis. 2024 ;100(s1): S363-S385

Fueling Alzheimer's Disease: Where Does Immunometabolism Stand?

Sónia C Correia, George Perry, Paula I Moreira.

  More than a century after the first description of Alzheimer's disease (AD), the road to a cure for this complex and heterogeneous neurodegenerative disorder has been paved by countless descriptive hypotheses and successive clinical trial failures. Auspiciously, the era of genome-wide association studies revolutionized the classical "neurocentric" view of AD by providing clues that brain-resident immune cells (i.e., microglia and astrocytes) are also key players in the pathological and clinical trajectory of this neurodegenerative disorder. Considering that the intercommunication among neurons, astrocytes, and microglia is fundamental for the functional organization of the brain, it is evident that the disruption of the proper functioning of this "triad" could contribute to the neuroinflammatory and neurodegenerative events that occur in the AD brain. Importantly, recent scientific progress in the burgeoning field of immunometabolism, a crossroad between metabolism and immune response, shed light on the importance of metabolic reprogramming of brain-resident immune cells in AD pathology. In this sense, the present review is aimed to summarize and discuss the current knowledge on the metabolic patterns of brain-resident immune cells during the AD continuum, putting a special focus on glucose, amino acids, and lipid metabolism. Changing the "old" picture of AD pathological basis by integrating the role of brain-resident immune cells it is imperative to establish new and feasible therapeutic interventions able to curb neuroinflammatory and neurodegenerative processes, and consequently cognitive deterioration.

Keywords:  Alzheimer’s disease; amino acids; astrocytes; glucose; lipids; metabolism; microglia

DOI:  https://doi.org/10.3233/JAD-240787
J Neuroinflammation. 2024 Aug 20. 21(1): 207

The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.

Melanie Ohm, Shirin Hosseini, Niklas Lonnemann, Wei He, Tushar More, Oliver Goldmann, Eva Medina, Karsten Hiller, Martin Korte.

  Despite advances in antimicrobial and anti-inflammatory treatment, inflammation and its consequences remain a major challenge in the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic inflammation has the potential to worsen the condition of body tissues and ultimately lead to significant impairment of their functionality. Although the central nervous system has long been considered immune privileged to peripheral immune responses, recent research has shown that strong immune responses in the periphery also affect the brain, leading to reactive microglia, which belong to the innate immune system and reside in the brain, and neuroinflammation. The inflammatory response is primarily a protective mechanism to defend against pathogens and tissue damage. However, excessive and chronic inflammation can have negative effects on neuronal structure and function. Neuroinflammation underlies the pathogenesis of many neurological and neurodegenerative diseases and can accelerate their progression. Consequently, targeting inflammatory signaling pathways offers potential therapeutic strategies for various neuropathological conditions, particularly Parkinson's and Alzheimer's disease, by curbing inflammation. Here the blood-brain barrier is a major hurdle for potential therapeutic strategies, therefore it would be highly advantageous to foster and utilize brain innate anti-inflammatory mechanisms. The tricarboxylic acid cycle-derived metabolite itaconate is highly upregulated in activated macrophages and has been shown to act as an immunomodulator with anti-inflammatory and antimicrobial functions. Mesaconate, an isomer of itaconate, similarly reduces the inflammatory response in macrophages. Nevertheless, most studies have focused on its esterified forms and its peripheral effects, while its influence on the CNS remained largely unexplored. Therefore, this study investigated the immunomodulatory and therapeutic potential of endogenously synthesized itaconate and its isomer mesaconate in lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show that both itaconate and mesaconate reduce LPS-induced neuroinflammation, as evidenced by lower levels of inflammatory mediators, reduced microglial reactivity and a rescue of synaptic plasticity, the cellular correlate of learning and memory processes in the brain. Overall, this study emphasizes that both itaconate and mesaconate have therapeutic potential for neuroinflammatory processes in the brain and are of remarkable importance due to their endogenous origin and production, which usually leads to high tolerance.

Keywords:  Hippocampus; LPS; Microglia; Neuroinflammation; Synaptic plasticity

DOI:  https://doi.org/10.1186/s12974-024-03188-3
Cell Rep. 2024 Aug 16. pii: S2211-1247(24)00986-0. [Epub ahead of print]43(8): 114636

Inherent preference for polyunsaturated fatty acids instigates ferroptosis of Treg cells that aggravates high-fat-diet-related colitis.

Junjie Yan, Yingying Zeng, Zerong Guan, Zhenhua Li, Shunchang Luo, Jie Niu, Junzhang Zhao, Haibiao Gong, Ting Huang, Zhongzhen Li, Anyi Deng, Qiong Wen, Jingyi Tan, Jun Jiang, Xiucong Bao, Sitao Li, Guodong Sun, Min Zhang, Min Zhi, Zhinan Yin, Wan-Yang Sun, Yi-Fang Li, Rong-Rong He, Guangchao Cao.

  Inflammatory bowel disease (IBD) has high prevalence in Western counties. The high fat content in Western diets is one of the leading causes for this prevalence; however, the underlying mechanisms have not been fully defined. Here, we find that high-fat diet (HFD) induces ferroptosis of intestinal regulatory T (Treg) cells, which might be the key initiating step for the disruption of immunotolerance and the development of colitis. Compared with effector T cells, Treg cells favor lipid metabolism and prefer polyunsaturated fatty acids (PUFAs) for the synthesis of membrane phospholipids. Therefore, consumption of HFD, which has high content of PUFAs such as arachidonic acid, cultivates vulnerable Tregs that are fragile to lipid peroxidation and ferroptosis. Treg-cell-specific deficiency of GPX4, the key enzyme in maintaining cellular redox homeostasis and preventing ferroptosis, dramatically aggravates the pathogenesis of HFD-induced IBD. Taken together, these studies expand our understanding of IBD etiology.

Keywords:  CP: Immunology; Ferroptosis; GPX4; High-fat Diet; IBD; Treg

DOI:  https://doi.org/10.1016/j.celrep.2024.114636
Science. 2024 Aug 23. 385(6711): 826-827

Alzheimer's and metabolism wed with IDO1.

Lance A Johnson, Shannon L Macauley.

Kynurenine pathway inhibition reverses deficits in Alzheimer's mouse models.

DOI: https://doi.org/10.1126/science.adr5836
Cell. 2024 Aug 14. pii: S0092-8674(24)00823-7. [Epub ahead of print]

Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment.

Meilin Zhu, Matthew W Frank, Christopher D Radka, Sarah Jeanfavre, Jiawu Xu, Megan W Tse, Julian Avila Pacheco, Jae Sun Kim, Kerry Pierce, Amy Deik, Fatima Aysha Hussain, Joseph Elsherbini, Salina Hussain, Nondumiso Xulu, Nasreen Khan, Vanessa Pillay, Caroline M Mitchell, Krista L Dong, Thumbi Ndung'u, Clary B Clish, Charles O Rock, Paul C Blainey, Seth M Bloom, Douglas S Kwon.

  Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the vaginal microbiota and enhances bacterial fitness by biochemically sequestering OA in a derivative form only ohyA-harboring organisms can exploit. OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metabolite-based treatment approach.

Keywords:  Lactobacillus; bacterial vaginosis; female genital tract; metabolism; vaginal microbiome; women’s health

DOI:  https://doi.org/10.1016/j.cell.2024.07.029
J Leukoc Biol. 2024 Aug 23. pii: qiae178. [Epub ahead of print]

Leukemia inhibitory factor drives transcriptional programs that promote lipid accumulation and M2 polarization in macrophages.

Visnu Chaparro, Louis-Philippe Leroux, Aurore Lebourg, Sophie Chagneau, Tyson E Graber, Tommy Alain, Maritza Jaramillo.

  Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, plays a central role in homeostasis and disease. Interestingly, some of the pleiotropic effects of LIF have been attributed to the modulation of macrophage functions although the molecular underpinnings have not been explored at a genome-wide scale. Herein, we investigated LIF-driven transcriptional changes in murine bone marrow-derived macrophages (BMDM) by RNA-seq. In silico analyses revealed a selective and time-dependent remodelling of macrophage gene expression programs associated with lipid metabolism and cell activation. Accordingly, a subset of LIF-upregulated transcripts related to cholesterol metabolism and lipid internalization was validated by RT-qPCR. This was accompanied by a LIF-enhanced capacity for lipid accumulation in macrophages upon incubation with oxidated low-density lipoprotein (Ox-LDL). Mechanistically, LIF triggered the phosphorylation (Y705 and S727) and nuclear translocation of the transcription factor STAT3 in BMDM. Consistent with this, Ingenuity Pathway Analysis (IPA) identified STAT3 as an upstream regulator of a subset of transcripts, including Il4ra, in LIF-treated macrophages. Notably, LIF priming enhanced BMDM responses to IL-4-mediated M2 polarization (i.e., increased arginase activity and accumulation of transcripts encoding for M2 markers). Conversely, LIF stimulation had no significant effect in BMDM responses to M1 polarizing stimuli (IFNγ and LPS). Thus, our study provides insight into the transcriptional landscape of LIF-treated macrophages, shedding light on its role in lipid metabolism and M2 polarization responses. A better understanding of the regulatory mechanisms governing LIF-driven changes might help informing novel therapeutic approaches aiming to reprogram macrophage phenotypes in diseased states (e.g., cancer, atherosclerosis, infection, etc.).

Keywords:  IL-4; Leukemia inhibitory factor (LIF); STAT3; cytokine; inflammation; lipids; macrophage; metabolism; polarization

DOI:  https://doi.org/10.1093/jleuko/qiae178
Mol Cancer Ther. 2024 Aug 20.

Targeting PDHK1 by DCA to restore NK cell function in hepatocellular carcinoma.

Xinyi Yang, Yuanyuan Liu, Peng Wang, Min Li, Tong Xiang, Songzuo Xie, Minxing Li, Yan Wang, Desheng Weng, Jingjing Zhao.

Pyruvate dehydrogenase complex is a crucial enzyme involved in the oxidation of glucose. It is regulated by pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase. Studies have demonstrated that pyruvate dehydrogenase kinase 1 (PDHK1), a key enzyme in glucose metabolism, behaves like oncogenes. It is highly expressed in tumors and is associated with poor patient prognosis. However, there is limited research on how PDHK1 affects immune cell function. We have established a model of natural killer (NK) cell exhaustion to investigate the impact of dichloroacetate (DCA) on NK cell function. The production of Granzyme B, IFN-γ, TNF-α, and CD107a by NK cells was explored by flow cytometry. The real-time live cell imaging system was used to monitor the ability of NK cells against tumor cells. The Seahorse analyzer was utilized to measure the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of NK cells. The mouse model was used to investigate the potential of combining DCA with adjuvant NK cell infusion. Our study demonstrated that the hepatocellular carcinoma (HCC) microenvironment mediated NK cellular exhaustion, high expression of PDHK1 and reduced cytokine secretion. We discovered that the PDHK1 inhibitor DCA enhances the activity and function of exhausted NK cells infiltrating the tumor microenvironment. Furthermore, in a subcutaneous HCC mouse model, DCA combined with NK cell treatment resulted in retarding cancer progression. This study indicates the potential of DCA in rescuing NK cell exhaustion and eliciting anti-tumor immunity.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0222
Nutr Metab (Lond). 2024 Aug 19. 21(1): 67

S-adenosyl-L-methionine supplementation alleviates aortic dissection by decreasing inflammatory infiltration.

Qian Wang, Jun An, Wei Zhou, Yujing Zhang, Jiang Huang, Geping Liao, Mingzhe Wang, Lingbo Xia, Aiping Le, Jianbing Zhu.

  Methionine, an indispensable amino acid crucial for dietary balance, intricately governs metabolic pathways. Disruption in its equilibrium has the potential to heighten homocysteine levels in both plasma and tissues, posing a conceivable risk of inducing inflammation and detriment to the integrity of vascular endothelial cells. The intricate interplay between methionine metabolism, with a specific focus on S-adenosyl-L-methionine (SAM), and the onset of thoracic aortic dissection (TAD) remains enigmatic despite acknowledging the pivotal role of inflammation in this vascular condition. In an established murine model induced by β-aminopropionitrile monofumarate (BAPN), we delved into the repercussions of supplementing with S-adenosyl-L-methionine (SAM) on the progression of TAD. Our observations uncovered a noteworthy improvement in aortic dissection and rupture rates, accompanied by a marked reduction in mortality upon SAM supplementation. Notably, SAM supplementation exhibited a considerable protective effect against BAPN-induced degradation of elastin and the extracellular matrix. Furthermore, SAM supplementation demonstrated a robust inhibitory influence on the infiltration of immune cells, particularly neutrophils and macrophages. It also manifested a notable reduction in the inflammatory polarization of macrophages, evident through diminished accumulation of MHC-IIhigh macrophages and reduced expression of inflammatory cytokines such as IL1β and TNFα in macrophages. Simultaneously, SAM supplementation exerted a suppressive effect on the activation of CD4 + and CD8 + T cells within the aorta. This was evidenced by an elevated proportion of CD44- CD62L + naïve T cells and a concurrent decrease in CD44 + CD62L- effector T cells. In summary, our findings strongly suggest that the supplementation of SAM exhibits remarkable efficacy in alleviating BAPN-induced aortic inflammation, consequently impeding the progression of thoracic aortic dissection.

Keywords:  Aortic dissection; Inflammation; Macrophage polarization; S-adenosyl-L-methionine; T cell activation

DOI:  https://doi.org/10.1186/s12986-024-00837-5
Exp Dermatol. 2024 Aug;33(8): e15159

Metabolic profiling of psoriasis vulgaris and palmoplantar pustulosis.

Yujin Lee, Seong Rae Kim, Mu Seong Ban, Howard Lee, Joo-Youn Cho, Seong Jin Jo.

Psoriasis is a chronic inflammatory skin disorder with various subtypes, including psoriasis vulgaris (PV) and palmoplantar pustulosis (PPP). Metabolomics studies have provided insights into psoriasis pathogenesis. However, research on metabolomic alterations in PV and PPP patients is limited. We aimed to explore and compare the metabolic profiles of patients with PV and PPP to those of healthy volunteers (HVs). A single-centre retrospective cohort was constructed, comprising Korean patients with psoriasis and HVs matched by age and sex. Clinical information including demographics, disease severity, and comorbidities were collected. Plasma samples were subjected to targeted metabolic analysis using an Absolute IDQ®p180 kit, which quantified 188 metabolites, including amino acids and carnitines. Statistical significance was assessed using an independent t-test and chi-square test, with p-values adjusted by the Benjamini-Hochberg procedure. Pathway analyses were employed to gain a comprehensive understanding of the metabolite profile. This study included 93 patients (73 PV and 20 PPP) and an equal number of HVs. PV patients showed increased levels of sarcosine, serotonin, propionylcarnitine, proline, aspartic acid, tyrosine, taurine, spermine and ornithine, but exhibited a decreased level of acetylcarnitine than matched HVs. Notably, sarcosine levels were significantly elevated in PPP patients. Furthermore, the sarcosine/glycine ratio was significantly higher in both PV and PPP patients than in HVs. Pathway analysis showed significant increases in metabolites involved in amino acid metabolism and the urea cycle in PV patients. In conclusion, this study demonstrated distinct metabolic profiles in PV and PPP patients compared to HVs, suggesting sarcosine as a potential biomarker for psoriasis.

DOI: https://doi.org/10.1111/exd.15159