bims-imicid 2025-01-05 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–01–05
twelve papers selected by
Dylan Ryan, University of Cambridge

Immunometabolic shifts in autoimmune disease: Mechanisms and pathophysiological implications.
Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
T cell metabolism in kidney immune homeostasis.
Engineering immunity using metabolically active polymeric nanoparticles.
Immunometabolism In Brain Aging and Neurodegeneration: Bridging Metabolic Pathways and Immune Responses.
Metabolic Reprograming of Macrophages: A New Direction in Traditional Chinese Medicine for Treating Liver Failure.
Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.
A postbiotic exopolysaccharide synergizes with Lactobacillus acidophilus to reduce intestinal inflammation in a mouse model of colitis.
Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.
The tryptophan metabolite kynurenic acid ameliorates septic colonic injury through activation of the PPARγ signaling pathway.
FOXP3 Transcriptionally Activates Fatty Acid Scavenger Receptor CD36 in Tumour-Induced Treg Cells.
The direct and indirect inhibition of proinflammatory adipose tissue macrophages by acarbose in diet-induced obesity.

Autoimmun Rev. 2024 Dec 30. pii: S1568-9972(24)00229-5. [Epub ahead of print] 103738

Immunometabolic shifts in autoimmune disease: Mechanisms and pathophysiological implications.

Yue Chen, Qingqing Lin, Hui Cheng, Qiyu Xiang, Wenxian Zhou, Jinyu Wu, Xiaobing Wang.

  Autoimmune diseases occur when the immune system abnormally attacks the body's normal tissues, causing inflammation and damage. Each disease has unique immune and metabolic dysfunctions during pathogenesis. In rheumatoid arthritis (RA), immune cells have different metabolic patterns and mitochondrial/lysosomal dysfunctions at different disease stages. In systemic lupus erythematosus (SLE), type I interferon (IFN) causes immune cell metabolic dysregulation, linking activation to metabolic shifts that may worsen the disease. In systemic sclerosis (SSc), mitochondrial changes affect fibroblast metabolism and the immune response. Idiopathic inflammatory myopathies (IIMs) patients have mitochondrial and metabolic issues. In primary Sjögren's syndrome (pSS), immune cell metabolism is imbalanced and mitochondrial damage can lead to cell/tissue damage. Metabolic reprogramming links cellular energy needs and immune dysfunctions, causing inflammation, damage, and symptoms in these diseases. It also affects immune cell functions like differentiation, proliferation, and secretion. This review discusses the potential of targeting metabolic pathways to restore immune balance, offering directions for future autoimmune disease research and treatment.

Keywords:  Autoimmune diseases; Idiopathic inflammatory myopathies; Metabolic reprogramming; Primary Sjögren's syndrome; Rheumatoid arthritis; Systemic lupus erythematosus; Systemic sclerosis

DOI:  https://doi.org/10.1016/j.autrev.2024.103738
Trends Endocrinol Metab. 2024 Dec 31. pii: S1043-2760(24)00321-7. [Epub ahead of print]

Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.

Letizia Rumiano, Teresa Manzo.

  Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.

Keywords:  CD8 T cells; antitumor immunity; immunotherapy; lipids; metabolism

DOI:  https://doi.org/10.1016/j.tem.2024.11.014
Front Immunol. 2024 ;15 1498808

T cell metabolism in kidney immune homeostasis.

Zikang Liu, Binbin Dai, Jiwen Bao, Yangbin Pan.

  Kidney immune homeostasis is intricately linked to T cells. Inappropriate differentiation, activation, and effector functions of T cells lead to a spectrum of kidney disease. While executing immune functions, T cells undergo a series of metabolic rewiring to meet the rapid energy demand. The key enzymes and metabolites involved in T cell metabolism metabolically and epigenetically modulate T cells' differentiation, activation, and effector functions, thereby being capable of modulating kidney immune homeostasis. In this review, we first summarize the latest advancements in T cell immunometabolism. Second, we outline the alterations in the renal microenvironment under certain kidney disease conditions. Ultimately, we highlight the metabolic modulation of T cells within kidney immune homeostasis, which may shed light on new strategies for treating kidney disease.

Keywords:  T cell; cellular metabolism; immune homeostasis; kidney disease; microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1498808
Trends Biotechnol. 2024 Dec 27. pii: S0167-7799(24)00345-7. [Epub ahead of print]

Engineering immunity using metabolically active polymeric nanoparticles.

Kate V Griffin, Michael N Saunders, Costas A Lyssiotis, Lonnie D Shea.

  Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.

Keywords:  immunoengineering; immunometabolism; metabolic reprogramming; polymeric nanoparticle

DOI:  https://doi.org/10.1016/j.tibtech.2024.11.016
Aging Dis. 2024 Dec 30.

Immunometabolism In Brain Aging and Neurodegeneration: Bridging Metabolic Pathways and Immune Responses.

Shokofeh Rahimpour, Briana L Clary, Sanaz Nasoohi, Yohanna S Berhanu, Candice M Brown.

The complex set of interactions between the immune system and metabolism, known as immunometabolism, has emerged as a critical regulator of disease outcomes in the central nervous system. Numerous studies have linked metabolic disturbances to impaired immune responses in brain aging, neurodegenerative disorders, and brain injury. In this review, we will discuss how disruptions in brain immunometabolism balance contribute to the pathophysiology of brain dysfunction. The first part of the review summarizes the contributions of critical immune cell populations such as microglia, astrocytes, and infiltrating immune cells in mediating inflammation and metabolism in CNS disorders. The remainder of the review addresses the impact of metabolic changes on immune cell activation and disease progression in brain aging, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, and traumatic brain injury. Furthermore, we also address the therapeutic potential of targeting immunometabolic pathways to reduce neuroinflammation and slow disease progression. By focusing on the interactions among brain immune cells and the metabolic mechanisms they recruit in disease, we present a comprehensive overview of brain immunometabolism in human health and disease.

DOI: https://doi.org/10.14336/AD.2024.1293
J Immunol Res. 2024 ;2024 5891381

Metabolic Reprograming of Macrophages: A New Direction in Traditional Chinese Medicine for Treating Liver Failure.

Junli Zhang, Na Li, Xiaoyu Hu.

  Acute liver failure (ALF) is a fulminant clinical syndrome that usually leads to multiple organ failure and high mortality. Macrophages play a crucial role in the initiation, development, and recovery of ALF. Targeting macrophages through immunotherapy holds significant promise as a therapeutic strategy. These cells exhibit remarkable plasticity, enabling them to differentiate into various subtypes based on changes in their surrounding microenvironment. M1-type macrophages are associated with a pro-inflammatory phenotype and primarily rely predominantly on glycolysis. In contrast, M2-type macrophages, which are characterized by anti-inflammatory phenotype, predominantly obtain their energy from oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Shifting macrophage metabolism from glycolysis to OXPHOS inhibits M1 macrophage activation and promotes M2 macrophage activation, thereby exerting anti-inflammatory and reparative effects. This study elucidates the relationship between macrophage activation and glucose metabolism reprograming from an immunometabolism perspective. A comprehensive literature review revealed that several signaling pathways may regulate macrophage polarization through energy metabolism, including phosphatidyl-inositol 3-kinase/protein kinase B (PI3K/AKT), mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α), nuclear factor-κB (NF-κB), and AMP-activated protein kinase (AMPK), which exhibit crosstalk with one another. Additionally, we systematically reviewed several traditional Chinese medicine (TCM) monomers that can modulate glucose metabolism reprograming and influence the polarization states of M1 and M2 macrophages. This review aimed to provide valuable insights that could contribute to the development of new therapies or drugs for ALF.

Keywords:  Chinese medicine; acute liver failure; glucose metabolism; macrophage polarization; signal transduction

DOI:  https://doi.org/10.1155/jimr/5891381
Nat Cardiovasc Res. 2025 Jan 02.

Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.

Matthew DeBerge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P Sullivan, Swapna Patil, Bo Ryung Lee, Minori I Thorp, Adam Mullick, Steve Yeh, Shuling Han, Anja M van der Laan, Hans W M Niessen, Xunrong Luo, Nicholas E S Sibinga, Edward B Thorp.

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species-dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.

DOI: https://doi.org/10.1038/s44161-024-00585-y
Int J Biol Macromol. 2024 Dec 26. pii: S0141-8130(24)09742-3. [Epub ahead of print] 138931

A postbiotic exopolysaccharide synergizes with Lactobacillus acidophilus to reduce intestinal inflammation in a mouse model of colitis.

Chong Ma, Xiaobin Zheng, Qian Zhang, Stephen James Renaud, Hansheng Yu, Yaning Xu, Yuchun Chen, Jing Gong, Yonghua Cai, Yanjun Hong, Hao Li, Qiongfeng Liao, Ying Guo, Liang Kang, Zhiyong Xie.

  Ulcerative colitis (UC) is an inflammatory bowel disease marked by gut inflammation and microbial dysbiosis. Exopolysaccharides (EPS) from probiotic bacteria have been shown to regulate microbial composition and metabolism, but their role in promoting probiotic growth and alleviating inflammation in UC remains unclear. Here, we investigate BLEPS-1, a novel EPS derived from Bifidobacterium longum subsp. longum XZ01, for its ability to promote the growth of Lactobacillus strains. We then tested a synbiotic formulation of BLEPS-1 and L. acidophilus in a DSS-induced UC mouse model. The combination of BLEPS-1 and L. acidophilus alleviated DSS-induced intestinal inflammation, outperforming either component alone. Administration of BLEPS-1 decreased the proportion of M1 macrophages in the intestine, while M2 macrophages were more abundant following L. acidophilus treatment. Together, BLEPS-1 and L. acidophilus synergistically modulated macrophage polarization toward the M2-type. Administration of BLEPS-1 and L. acidophilus together modulated gut microbiota composition and altered the gut metabolic profile, with BLEPS-1 and L. acidophilus promoting metabolism of short-chain fatty acids and aromatic amino acids, respectively. Our study identified a novel synbiotic formulation with potent immunomodulatory and metabolic activity, laying the groundwork for a promising therapeutic strategy to treat intestinal inflammatory diseases such as colitis.

Keywords:  Aromatic amino acid metabolites; Colitis; Exopolysaccharides; Macrophage polarization; Postbiotic; Synbiotic

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138931
Int Immunopharmacol. 2024 Dec 30. pii: S1567-5769(24)02414-7. [Epub ahead of print]147 113892

Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.

Yulin Wang, Qiutong Dong, Menghan Yuan, Jingxian Hu, Peizhe Lin, Yijing Yan, Yu Wang, Yanyan Wang.

  Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.

Keywords:  Breast cancer; Immunity; Metabolism; Myeloid-derived suppressor cells; Targeted therapy

DOI:  https://doi.org/10.1016/j.intimp.2024.113892
Int Immunopharmacol. 2024 Dec 31. pii: S1567-5769(24)02173-8. [Epub ahead of print]147 113651

The tryptophan metabolite kynurenic acid ameliorates septic colonic injury through activation of the PPARγ signaling pathway.

Fei Wang, Meng Zhang, Liping Yin, Ziyang Zhou, Ziyao Peng, Wenweiran Li, Hui Chen, Guohong Yu, Jianguo Tang.

  Sepsis is the leading cause of death among critically ill patients in clinical practice, making it urgent to reduce its incidence and mortality rates. In sepsis, macrophage dysfunction often worsens and complicates the condition. M1 and M2 macrophages, two distinct types, contribute to pro-inflammatory and anti-inflammatory effects, respectively. An imbalance between them is a major cause of sepsis. The aim of this study was to explore the potential of a differential metabolite between M1 and M2 macrophages in mitigating septic colonic injury via multiomics in combination with clinical data and animal experiments. Using nontargeted metabolomics analysis, we found that Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, was significantly upregulated in the supernatant of M2 macrophages. Furthermore, we discovered that the level of KYNA was significantly decreased in sepsis in both human and mouse serum and was negatively correlated with inflammatory factor levels. In vivo experiments demonstrated that KYNA can effectively alleviate septic colon injury and reduce inflammatory factor levels in mice, indicating that KYNA plays a very important protective role in sepsis. Mechanistically, KYNA promotes the transition of M1 macrophages to M2 macrophages by inhibiting the NF-κB signaling pathway and alleviates septic colonic injury through the PPARγ/NF-κB axis. This article reveals that KYNA, a differentially abundant metabolite between M1 and M2 macrophages, can become a new strategy for alleviating septic colon injury.

Keywords:  Kynurenic acid; M1 macrophages; M2 macrophages; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2024.113651
Immunology. 2024 Dec 30.

FOXP3 Transcriptionally Activates Fatty Acid Scavenger Receptor CD36 in Tumour-Induced Treg Cells.

Subhanki Dhar, Tania Sarkar, Sayantan Bose, Subhadip Pati, Dwaipayan Chakraborty, Dia Roy, Abir K Panda, Aharna Guin, Sumon Mukherjee, Kuladip Jana, Diptendra K Sarkar, Gaurisankar Sa.

  The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4+ Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.

Keywords:  CD36; Treg; cancer; metabolism; tumour microenvironment

DOI:  https://doi.org/10.1111/imm.13887
Cell Rep Med. 2024 Dec 24. pii: S2666-3791(24)00654-2. [Epub ahead of print] 101883

The direct and indirect inhibition of proinflammatory adipose tissue macrophages by acarbose in diet-induced obesity.

Xiaohui Li, Shimeng Zheng, Haozhe Xu, Zihan Zhang, Xiaotong Han, Yunxiong Wei, Hua Jin, Xiaonan Du, Hufeng Xu, Mengyi Li, Zhongtao Zhang, Songlin Wang, Guangyong Sun, Dong Zhang.

  Inflammation is critical for obesity and obesity-induced insulin resistance (IR). In this study, we reveal the function and mechanism of acarbose on adipose tissue macrophage (ATM)-mediated inflammation in obesity and obesity-induced IR. First, acarbose enhances the abundance of propionic acid-producing Parasutterella, therefore indirectly inhibiting the survival and proinflammatory function of M1-like ATMs via GPR43. Most interestingly, acarbose can directly inhibit M1-like ATM-mediated inflammation through GPR120. Diet-induced obese mice exhibit nitrobenzoxadiazoles (NBD) fluorescence-labeled ATMs, but lean mice that also orally received NBD fluorescence-labeled acarbose do not exhibit NBD fluorescence-labeled ATMs. This direct inhibition of macrophages by acarbose is validated in mouse and human macrophages in vitro. In conclusion, our study reveals that acarbose directly and indirectly inhibits proinflammatory macrophage phenotype, which contributes to the improvement of obesity and obesity-induced IR. The understanding of the immune regulatory effects of acarbose may extend its potential for further therapeutic applications.

Keywords:  Parasutterella excrementihominis; acarbose; adipose tissue macrophages; obesity; propionic acid

DOI:  https://doi.org/10.1016/j.xcrm.2024.101883