bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024‒10‒13
sixteen papers selected by
Dylan Ryan, University of Cambridge
  1. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
  2. Histone lactylation drives CD8+ T cell metabolism and function.
  3. Human tissue-resident NK cells in the lung have a higher glycolytic capacity than non-tissue-resident NK cells in the lung and blood.
  4. Toxicity of extracellular cGAMP and its analogs to T cells is due to SLC7A1-mediated import.
  5. Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.
  6. Metabolic regulation of the immune system in health and diseases: mechanisms and interventions.
  7. Metabolism and macrophages in the tumor microenvironment.
  8. Microbiota-derived acetate is associated with functionally optimal virus-specific CD8+ T cell responses to influenza virus infection via GPR43-dependent metabolic reprogramming.
  9. Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.
  10. Siglec-G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy.
  11. Lactate's impact on immune cells in sepsis: unraveling the complex interplay.
  12. CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
  13. Bergenin, the main active ingredient of Bergenia purpurascens, attenuates Th17 cell differentiation by downregulating fatty acid synthesis.
  14. Flaviviruses manipulate mitochondrial processes to evade the innate immune response.
  15. Exploring the circulating metabolome of sepsis: metabolomic and lipidomic profiles sampled in the ambulance.
  16. The kynurenine pathway in patients with rheumatoid arthritis during tumor necrosis factor α inhibitors treatment.
  1. Nat Commun. 2024 Oct 06. 15(1): 8658
    GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
    Justin A Guerrero, Dorota D Klysz, Yiyun Chen, Meena Malipatlolla, Jameel Lone, Carley Fowler, Lucille Stuani, Audre May, Malek Bashti, Peng Xu, Jing Huang, Basil Michael, Kévin Contrepois, Shaurya Dhingra, Chris Fisher, Katrin J Svensson, Kara L Davis, Maya Kasowski, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
    DOI:  https://doi.org/10.1038/s41467-024-52666-y
  2. Nat Immunol. 2024 Oct 07.
    Histone lactylation drives CD8+ T cell metabolism and function.
    Deblina Raychaudhuri, Pratishtha Singh, Bidisha Chakraborty, Mercedes Hennessey, Aminah J Tannir, Shrinidhi Byregowda, Seanu Meena Natarajan, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.
      The activation and functional differentiation of CD8+ T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+ T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+ T cells, which act as transcription initiators of key genes regulating CD8+ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01985-9
  3. Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2412489121
    Human tissue-resident NK cells in the lung have a higher glycolytic capacity than non-tissue-resident NK cells in the lung and blood.
    Gráinne Jameson, Aaron Walsh, Robbie Woods, Isabella Batten, Dearbhla M Murphy, Sarah A Connolly, Emily Duffin, Oisin O'Gallchobhair, Parthiban Nadarajan, Finbarr O'Connell, Laura E Gleeson, Joseph Keane, Sharee A Basdeo.
      Tissue-resident natural killer (trNK) cells are present in the human lung, yet their metabolic function is unknown. NK cell effector and metabolic function are intrinsically linked therefore targeting metabolism presents therapeutic potential in supporting NK cell effector function. This study identifies trNK cells in human bronchoalveolar lavage fluid (BALF) and reveals their distinct metabolic function. To assess the differential phenotype and metabolism of NK cells in the lung, human BALF, and peripheral blood were evaluated by flow cytometry and SCENITHTM. Published RNA-sequencing datasets of human lung and blood NK cells were repurposed to determine their differential gene expression. We identified CD49a+CD69+CD103+/-CD56brightCD16- trNK cells in human BALF samples and metabolic profiling revealed that lung CD56brightCD16- NK cells' glycolytic capacity and dependence on glucose is significantly higher than matched peripheral blood counterparts. This high glycolytic capacity and glucose dependence was attributed to the trNK cell subset which supports the existing evidence that they have an enhanced ability to respond in the lung.
    Keywords:  NK cells; immunometabolism; lung; tissue-resident
    DOI:  https://doi.org/10.1073/pnas.2412489121
  4. bioRxiv. 2024 Sep 24. pii: 2024.09.21.614248. [Epub ahead of print]
    Toxicity of extracellular cGAMP and its analogs to T cells is due to SLC7A1-mediated import.
    Valentino Sudaryo, Dayanne R Carvalho, J Michelle Lee, Jacqueline A Carozza, Xujun Cao, Anthony F Cordova, Lingyin Li.
      STING agonists are promising innate immune therapies and can synergize with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. An important class of STING agonists are analogs of the endogenous STING agonist, cGAMP, and while transporters for these small molecules are known in some cell types, how they enter and kill T cells remains unknown. Here, we identify the cationic amino acid transporter SLC7A1 as the dominant transporter of cGAMP and its analogs in activated primary mouse and human T cells. T cells upregulate this transporter upon activation and rapid proliferation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. To circumvent the essentiality of SLC7A1 to proliferating T cells, we found that the residues responsible for cGAMP transport are separate from the arginine binding pocket allowing us to perturb cGAMP transport and STING-activation mediated killing without impacting arginine transport. These results suggest that SLC7A1 is a potential target for alleviating T cell toxicity associated with cGAMP and its analogs.
    DOI:  https://doi.org/10.1101/2024.09.21.614248
  5. Heliyon. 2024 Sep 30. 10(18): e38018
    Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.
    Hongbo Ma, Limei Gao, Rong Chang, Lihong Zhai, Yanli Zhao.
      Immune metabolism is a result of many specific metabolic reactions, such as glycolysis, the tricarboxylic acid (TCA) pathway, the pentose phosphate pathway (PPP), mitochondrial oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), fatty acid biosynthesis (FAs) and amino acid pathways, which promote cell proliferation and maintenance with structural and pathological energy to regulate cellular signaling. The metabolism of macrophages produces many metabolic intermediates that play important regulatory roles in tissue repair and regeneration. The metabolic activity of proinflammatory macrophages (M1) mainly depends on glycolysis and the TCA cycle system, but anti-inflammatory macrophages (M2) have intact functions of the TCA cycle, which enhances FAO and is dependent on OXPHOS. However, the metabolic mechanisms of macrophages in tissue repair and regeneration have not been well investigated. Thus, we review how three main metabolic mechanisms of macrophages, glucose metabolism, lipid metabolism, and amino acid metabolism, regulate tissue repair and regeneration.
    Keywords:  Amino acid metabolism; Glucose metabolism; Lipid metabolism; Macrophages; Tissue repair and regeneration
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38018
  6. Signal Transduct Target Ther. 2024 Oct 09. 9(1): 268
    Metabolic regulation of the immune system in health and diseases: mechanisms and interventions.
    Tengyue Hu, Chang-Hai Liu, Min Lei, Qingmin Zeng, Li Li, Hong Tang, Nannan Zhang.
      Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.
    DOI:  https://doi.org/10.1038/s41392-024-01954-6
  7. Curr Opin Immunol. 2024 Oct 04. pii: S0952-7915(24)00081-5. [Epub ahead of print]91 102491
    Metabolism and macrophages in the tumor microenvironment.
    Hannah Yang, Chan Kim, Weiping Zou.
      Tumor-associated macrophages (TAMs) constitute the primary subset of immune cells within the tumor microenvironment (TME). Exhibiting both phenotypic and functional heterogeneity, TAMs play distinct roles in tumor initiation, progression, and responses to therapy in patients with cancer. In response to various immune and metabolic cues within the TME, TAMs dynamically alter their metabolic profiles to adapt. Changes in glucose, amino acid, and lipid metabolism in TAMs, as well as their interaction with oncometabolites, not only sustain their energy demands but also influence their impact on tumor immune responses. Understanding the molecular mechanisms underlying the metabolic reprogramming of TAMs and their orchestration of metabolic processes can offer insights for the development of novel cancer immunotherapies targeting TAMs. Here, we discuss how metabolism reprograms macrophages in the TME and review clinical trials aiming to normalize metabolic alterations in TAMs and alleviate TAM-mediated immune suppression and protumor activity.
    DOI:  https://doi.org/10.1016/j.coi.2024.102491
  8. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2401649
    Microbiota-derived acetate is associated with functionally optimal virus-specific CD8+ T cell responses to influenza virus infection via GPR43-dependent metabolic reprogramming.
    Jingjing Qiu, Chunwei Shi, Yanan Zhang, Tianming Niu, Shuxian Chen, Guilian Yang, Shu Jeffrey Zhu, Chunfeng Wang.
      The microbiota-associated factors that affect host susceptibility and adaptive immunity to influenza A virus (IAV) infection have not been fully elucidated. By comparing the microbiota composition between survivors and mice that succumbed to IAV strain PR8 infection, we identified that the commensal bacterium Blautia coccoides protects antibiotics (Abx)-treated or germ-free (GF) mice from PR8 infection by inducing functionally optimal virus-specific CD8+ T cell responses. Administration of exogenous acetate reproduced the protective effect of B. coccoides monocolonization in Abx and GF mice, enhancing oxidative phosphorylation and glycolysis as well as secretion of IFN-γ and granzyme B in virus-specific CD8+ T cells, dependent on GPR43 signaling and acetyl-CoA synthetase 2. Thus, we have demonstrated that microbiota-derived acetate possesses an antiviral effect that induces an optimal virus-specific CD8+ T cell response to IAV PR8 infection via GPR43-dependent metabolic reprogramming.
    Keywords:  Blautia coccoides; GPR43; acetate; influenza virus; metabolic reprogramming; virus-specific CD8+ T cells
    DOI:  https://doi.org/10.1080/19490976.2024.2401649
  9. Small. 2024 Oct 10. e2406870
    Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.
    Yang Liu, Hui Li, Yan-Yun Hao, Ling-Ling Huang, Xia Li, Jing Zou, Shi-Ying Zhang, Xiao-Yue Yang, Hong-Fei Chen, Yi-Xuan Guo, Yun-Yan Guan, Zhi-Yue Zhang.
      The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.
    Keywords:  TLR7/8; immune therapy; lactate metabolism; monocarboxylate transporters 4 (MCT4); nano‐dispatcher
    DOI:  https://doi.org/10.1002/smll.202406870
  10. Adv Sci (Weinh). 2024 Oct 07. e2403438
    Siglec-G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy.
    Shenhui Yin, Chunzhen Li, Xin Shen, Guanyu Yu, Likun Cui, Yunyang Wu, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Cheng Qian, Zui Zou, Yizhi Yu, Sheng Xu.
      CD8+ T cells play a critical role in cancer immune-surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain-3 (Tim-3). Here Siglec-G is identified as a coinhibitory receptor that limits CD8+ T cell function. Siglec-G is highly expressed on tumor-infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec-G-SHP2 axis in CD8+ T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec-G in inhibiting CD8+ T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy.
    Keywords:  CD8+ T cells; Siglec‐G; metabolic rewiring; tumor immunotherapy
    DOI:  https://doi.org/10.1002/advs.202403438
  11. Front Immunol. 2024 ;15 1483400
    Lactate's impact on immune cells in sepsis: unraveling the complex interplay.
    Tao Zhang, Linjian Chen, Gatkek Kueth, Emily Shao, Xiaohui Wang, Tuanzhu Ha, David L Williams, Chuanfu Li, Min Fan, Kun Yang.
      Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes.
    Keywords:  immune cells; immune response; immunosuppression; inflammation; lactate; lactic acid; lactylation; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2024.1483400
  12. Immunometabolism (Cobham). 2024 Oct;6(4): e00048
    CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
    Connor S R Jankowski, Thomas Weichhart.
      Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.
    Keywords:  CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000048
  13. FASEB J. 2024 Oct 15. 38(19): e70095
    Bergenin, the main active ingredient of Bergenia purpurascens, attenuates Th17 cell differentiation by downregulating fatty acid synthesis.
    Yue He, Danlei Xu, Jing Zhang, Yan Liu, Minghui Liao, Yufeng Xia, Zhifeng Wei, Yue Dai.
      Bergenin is the main active ingredient of Bergenia purpurascens, a medicinal plant which has long been used to treat a variety of Th17 cell-related diseases in China, such as allergic airway inflammation and colitis. This study aimed to uncover the underlying mechanisms by which bergenin impedes Th17 cell response in view of cellular metabolism. In vitro, bergenin treatment reduced the frequency of Th17 cells generated from naïve CD4+ T cells of mice. Mechanistically, bergenin preferentially restrained fatty acid synthesis (FAS) but not other metabolic pathways in differentiating Th17 cells, and exogenous addition of either palmitic acid (PA) or oleic acid (OA) and combination with acetyl-CoA carboxylase 1 (ACC1) activator citric acid dampened the inhibition of bergenin on Th17 cell differentiation. Bergenin inhibited FAS through downregulating the expression of SREBP1 via restriction of histone H3K27 acetylation in the SREBP1 promoter, and SREBP1 overexpression weakened the inhibition of bergenin on Th17 differentiation. Furthermore, bergenin was shown to directly interact with SIRT1 and result in activation of SIRT1. Either combination with SIRT1 inhibitor EX527 or point mutation plasmid of SIRT1 diminished the inhibitory effect of bergenin on FAS and Th17 cell differentiation. Finally, the inhibitory effect of bergenin on Th17 cell response and SIRT1 dependence were verified in mice with dextran sulfate sodium-induced colitis. In short, bergenin repressed Th17 cell response by downregulating FAS via activation of SIRT1, which might find therapeutic use in Th17 cell-related diseases.
    Keywords:  SIRT1; Th17 cells; bergenin; fatty acid synthesis; ulcerative colitis
    DOI:  https://doi.org/10.1096/fj.202400961R
  14. Npj Viruses. 2024 ;2(1): 47
    Flaviviruses manipulate mitochondrial processes to evade the innate immune response.
    RuthMabel Boytz, Kadiatou Keita, Joanna B Pawlak, Maudry Laurent-Rolle.
      Mitochondria are essential eukaryotic organelles that regulate a range of cellular processes, from metabolism to calcium homeostasis and programmed cell death. They serve as essential platforms for antiviral signaling proteins during the innate immune response to viral infections. Mitochondria are dynamic structures, undergoing frequent fusion and fission processes that regulate various aspects of mitochondrial biology, including innate immunity. Pathogens have evolved sophisticated mechanisms to manipulate mitochondrial morphology and function to facilitate their replication. In this review, we examine the emerging literature on how flaviviruses modulate mitochondrial processes.
    Keywords:  Immunology; Microbiology
    DOI:  https://doi.org/10.1038/s44298-024-00057-x
  15. Metabolomics. 2024 Oct 05. 20(5): 111
    Exploring the circulating metabolome of sepsis: metabolomic and lipidomic profiles sampled in the ambulance.
    Samira Salihovic, Daniel Eklund, Robert Kruse, Ulrika Wallgren, Tuulia Hyötyläinen, Eva Särndahl, Lisa Kurland.
      BACKGROUND: Sepsis is defined as a dysfunctional host response to infection. The diverse clinical presentations of sepsis pose diagnostic challenges and there is a demand for enhanced diagnostic markers for sepsis as well as an understanding of the underlying pathological mechanisms involved in sepsis. From this perspective, metabolomics has emerged as a potentially valuable tool for aiding in the early identification of sepsis that could highlight key metabolic pathways and underlying pathological mechanisms.OBJECTIVE: The aim of this investigation is to explore the early metabolomic and lipidomic profiles in a prospective cohort where plasma samples (n = 138) were obtained during ambulance transport among patients with infection according to clinical judgement who subsequently developed sepsis, patients who developed non-septic infection, and symptomatic controls without an infection.
    METHODS: Multiplatform metabolomics and lipidomics were performed using UHPLC-MS/MS and UHPLC-QTOFMS. Uni- and multivariable analysis were used to identify metabolite profiles in sepsis vs symptomatic control and sepsis vs non-septic infection.
    RESULTS: Univariable analysis disclosed that out of the 457 annotated metabolites measured across three different platforms, 23 polar, 27 semipolar metabolites and 133 molecular lipids exhibited significant differences between patients who developed sepsis and symptomatic controls following correction for multiple testing. Furthermore, 84 metabolites remained significantly different between sepsis and symptomatic controls following adjustment for age, sex, and Charlson comorbidity score. Notably, no significant differences were identified in metabolites levels when comparing patients with sepsis and non-septic infection in univariable and multivariable analyses.
    CONCLUSION: Overall, we found that the metabolome, including the lipidome, was decreased in patients experiencing infection and sepsis, with no significant differences between the two conditions. This finding indicates that the observed metabolic profiles are shared between both infection and sepsis, rather than being exclusive to sepsis alone.
    Keywords:  Ambulance; Infection; Lipidomics; Metabolomics; Plasma; Sepsis
    DOI:  https://doi.org/10.1007/s11306-024-02172-5
  16. Reumatologia. 2024 ;62(4): 220-225
    The kynurenine pathway in patients with rheumatoid arthritis during tumor necrosis factor α inhibitors treatment.
    Joanna Witoszyńska-Sobkowiak, Dorota Sikorska, Karolina Niklas, Iwona Żychowska, Rafał Rutkowski, Włodzimierz Samborski.
      Introduction: The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis (RA). The aim of the study was to evaluate the effect of treatment with tumor necrosis factor α (TNF-α) inhibitors on the activity of the kynurenine pathway in patients with RA.Material and methods: This was an investigator-initiated, prospective, observational study. The study was performed on 30 RA patients (Caucasian, 11 male, 19 female; mean age 45 ±16 years) treated with TNF-α inhibitors. All patients were assessed before and after 6 months of therapy. As a control group, age- and sex-matched, 20 healthy volunteers were recruited. Disease activity was evaluated by the Modified Disease Activity Score with 28-joint count (DAS28). Inflammatory markers were assessed routinely by the hospital central laboratory. Serum concentrations of kynurenine, serotonin and tryptophan were measured with specific immunoassays. To estimate indoleamine 2,3-dioxygenase (IDO) activity, kynurenine-to-tryptophan ratio was calculated.
    Results: The results of our study showed changes in tryptophan metabolism in RA patients, compared with healthy controls. Surprisingly, RA patients had statistically significant decreased kynurenine-to-tryptophan ratio (p = 0.003), which could indicate diminished IDO activation in RA. Moreover, we found no significant changes in kynurenine-to-tryptophan ratio after treated with TNF-α inhibitors (p = 0.490), despite disease remission. Additionally, tryptophan metabolism activity did not correlate with objective markers of inflammation.
    Conclusions: The RA patients had altered tryptophan metabolism, compared with healthy controls. The mechanisms affecting tryptophan metabolism in RA may be complex. We believe that continuing elucidation of pathophysiological pathways relevant in RA offer substantial hope for the development of specific pharmacotherapy for treatment of RA - especially for comorbidity of RA and depression.
    Keywords:  biologic treatment; depression; kynurenine pathway; rheumatoid arthritis
    DOI:  https://doi.org/10.5114/reum/191752
This page is being maintained by Thomas Krichel. It was last updated on 2024‒10‒15 at 15:52.