bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2021‒12‒12
twenty-two papers selected by
Dylan Ryan
University of Cambridge

  1. Curr Hypertens Rep. 2021 Dec 09. 23(12): 45
      PURPOSE OF REVIEW: In this article, we summarize the current literature supporting metabolic and redox signaling pathways as important mechanisms underlying T cell activation in the context of hypertension.RECENT FINDINGS: T cell immunometabolism undergoes dramatic remodeling in order to meet the demands of T cell activation, differentiation, and proliferation. Recent evidence demonstrates that the T cell oxidation-reduction (redox) system also undergoes significant changes upon activation, which can itself modulate metabolic processes and T cell function. Dysregulation of these signaling pathways can lead to aberrant T cell activation and inappropriate ROS production, both of which are linked to pathological conditions like hypertension. While the contribution of T cells to the progression of hypertension has been thoroughly investigated, how T cell metabolism and redox signaling changes, both separately and together, is an area of study that remains largely untouched. This review presents evidence from our own laboratory as well as others to highlight the importance of these two mechanisms in the study of hypertension.
    Keywords:  Hypertension; Immune cells; Immunometabolism; Redox signaling; T cells
  2. Cell Mol Immunol. 2021 Dec 07.
      Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
    Keywords:  Tissue macrophages; homeostasis; metabolism; pathology; tissue regeneration
  3. J Immunol. 2021 Dec 10. pii: ji2100514. [Epub ahead of print]
      T cells must shift their metabolism to respond to infections and tumors and to undergo memory formation. The ATP-binding cassette transporter ABCB10 localizes to the mitochondrial inner membrane, where it is thought to export a substrate important in heme biosynthesis and metabolism, but its role in T cell development and activation is unknown. In this article, we use a combination of methods to study the effect of ABCB10 loss in primary and malignantly transformed T cells. Although Abcb10 is dispensable for development of both CD4+ and CD8+ T cells, it is required for expression of specific cytokines in CD4+, but not CD8+, T cells activated in vitro. These defects in cytokine expression are magnified on repeated stimulation. In vivo, CD8+ cells lacking ABCB10 expand more in response to viral infection than their control counterparts, while CD4+ cells show reductions in both number and percentage. CD4+ cells lacking ABCB10 show impairment in Ag-specific memory formation and recall responses that become more severe with time. In malignant human CD4+ Jurkat T cells, we find that CRISPR-mediated ABCB10 disruption recapitulates the same cytokine expression defects upon activation as observed in primary mouse T cells. Mechanistically, ABCB10 deletion in Jurkat T cells disrupts the ability to switch to aerobic glycolysis upon activation. Cumulatively, these results show that ABCB10 is selectively required for specific cytokine responses and memory formation in CD4+ T cells, suggesting that targeting this molecule could be used to mitigate aberrant T cell activation.
  4. Elife. 2021 Dec 09. pii: e71978. [Epub ahead of print]10
      Legionella pneumophila, the causative agent of Legionnaires'; disease, a severe pneumonia, injects via a type-IV-secretion-system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δψm) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial FOF1-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δψm, preserves mitochondrial polarization and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that LpSpl is partially involved in conserving the Δψm, but not LncP and MitF. The inhibition of the L. pneumophila-induced 'reverse mode' of the FOF1-ATPase collapsed the Δψm and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δψm and showed delayed cell death. This direct manipulation of the mode of activity of the FOF1-ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.
    Keywords:  infectious disease; microbiology
  5. Cancers (Basel). 2021 Nov 24. pii: 5912. [Epub ahead of print]13(23):
      Over the past decade, advances in cancer immunotherapy through PD1-PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.
    Keywords:  cancer; immune response; immunotherapy; metabolic drug; metabolism
  6. Cell Rep. 2021 Dec 07. pii: S2211-1247(21)01574-6. [Epub ahead of print]37(10): 110083
      Robust expansion of adoptively transferred T cells is a prerequisite for effective cancer immunotherapy, but how many genes in the genome modulate T cell expansion remains unknown. Here, we perform in vivo and in vitro CRISPR screens to systematically identify genes influencing CD8 T cell expansion. In the mouse genome, ∼2,600 and ∼1,500 genes are required for optimal CD8 T cell expansion in vivo and in vitro, respectively. In vivo-specific CD8 T cell essential genes are enriched in metabolic pathways, including mitochondrial metabolism. The strongest repressor of CD8 T cell expansion is Roquin, the ablation of which drastically boosts T cell proliferation by enhancing cell-cycle progression and upregulation of IRF4. Roquin deficiency or IRF4 overexpression potently enhances anti-tumor immunity. These data provide a functional catalog of CD8 T cell fitness genes and suggest that targeting the Roquin-IRF4 axis is an effective strategy to enhance efficacy of adoptive transfer therapy for cancer.
    Keywords:  CRISPR screen; IRF4; Rc3h1; Roquin; T cell expansion; adoptive cell transfer; cancer immunotherapy; essential gene; fitness gene; lymphodepletion
  7. Nat Commun. 2021 Dec 08. 12(1): 7115
      Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.
  8. Cell Metab. 2021 Dec 07. pii: S1550-4131(21)00535-0. [Epub ahead of print]33(12): 2307-2309
      There are dramatic disparities in infection susceptibility within populations. In this issue of Cell Metabolism, Zhao and Karpac uncover a muscle-adipose-gut axis in Drosophila that explains variability in pathogen susceptibility. They show that the degree of intramuscular NF-κB activation accounts for differences in circulating glutamate, which enhances infection resistance at the expense of reproduction.
  9. Front Immunol. 2021 ;12 747780
      Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.
    Keywords:  Breg cells; IDO; L-Kynurenine; MDSC (myeloid-derived suppressor cells); TME (tumor microenvironment); aryl hydrocarbon receptor (AhR); immunosuppression; lung cancer
  10. Immunol Cell Biol. 2021 Dec 09.
      Regulatory T cells (Tregs) are a specialised immune cell type that plays important roles in regulating immune responses. However, those found in adipose tissue, particularly visceral adipose tissue (VAT), have also been shown to exert metabolic regulatory functions. In this study, we investigate the requirement of the miR-17~92a cluster of microRNAs in VAT Tregs and the impact on blood glucose. This cluster of microRNAs is one that we previously showed to be important for the fitness of Tregs found in secondary lymphoid organs. We found that male mice with Treg-specific miR-17~92a deficiency are resistant to impaired glucose tolerance induced by a high-fat diet. However, high-fat feeding still impaired glucose tolerance in female mice with Treg-specific miR-17~92a deficiency. There was an increase in KLRG1- naïve Tregs and a loss of KLRG1+ terminally differentiated Tregs in the VAT of Treg-specific miR-17~92a deficient male mice but not female mice. The protection of male mice from high-fat feeding was also associated with increased IL-10 and reduced IFNγ expression by conventional CD4+ T cells and reduced IL-2 expression by both CD4+ and CD8+ T cells in the VAT. Together this suggests that expression of miR-17~92a by VAT Tregs regulates the effector phenotype of conventional T cells and in turn the metabolic function of adipose tissue and blood glucose homeostasis.
    Keywords:  MicroRNA; adipose tissue; blood glucose; regulatory T cells
  11. Cell Metab. 2021 Dec 07. pii: S1550-4131(21)00538-6. [Epub ahead of print]33(12): 2415-2427.e6
      Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8+ T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity.
    Keywords:  CD8(+) T cells; IL-22; Tc1; Tc17; Tc22; anti-PD1; coenzyme A; immunometabolism; immunotherapy; pantothenate
  12. J Agric Food Chem. 2021 Dec 09.
      Itaconate is a promising new candidate for anti-inflammatory and metabolic reprogramming, and 4-octyl itaconate (OI) is a cell-permeable itaconate derivative. To investigate the effect of OI in inflammatory response and glycolipid metabolism, we fed gibel carp with a 40% dietary soybean meal diet containing 0.1% OI (SBM + 0.1OI) or not (SBM) and compared these with fishmeal (FM) as reference. Compared with FM, dietary SBM decreased the growth performance, induced inflammation in the intestine and liver, and decreased the glucose utilization ability of the liver. However, 0.1% OI supplementation in SBM significantly increased the growth performance (from 20.11 ± 0.77 to 23.33 ± 0.45 g, P < 0.05), reduced inflammation in different organs through Nrf2 activation, and alleviated SBM-induced high plasma glucose (from 6.06 ± 0.23 to 4.37 ± 0.14 g, P < 0.05) and low crude body lipid (from 4.08 ± 0.17 to 4.91 ± 0.10 g, P < 0.05). Multi-omics revealed that OI had obvious effects on carbohydrate metabolism. OI regulates peroxisome proliferator-activated receptor gamma (ppar-γ), and its target genes (glut2 and gk) enhance liver glycolysis and lipid de novo lipogenesis, which are also dependent on Nrf2 activation. To conclude, dietary 0.1% OI can promote the growth of gibel carp and alleviate foodborne intestinal and hepatic inflammation and abnormal glycolipid metabolism by Nrf2-regulated Pparγ expression.
    Keywords:  4-octyl itaconate; glycolipid metabolism; inflammation; regulatory pathways; soybean meal
  13. J Am Heart Assoc. 2021 Dec 07. e023227
      Background The complexity of the interaction between metabolic dysfunction and cardiovascular complications has long been recognized to extend beyond simple perturbations of blood glucose levels. Yet, structured interventions targeting the root pathologies are not forthcoming. Growing evidence implicates the inflammatory changes occurring in perivascular adipose tissue (PVAT) as early instigators of cardiovascular deterioration. Methods and Results We used a nonobese prediabetic rat model with localized PVAT inflammation induced by hypercaloric diet feeding, which dilutes inorganic phosphorus (Pi) to energy ratio by 50%, to investigate whether Pi supplementation ameliorates the early metabolic impairment. A 12-week Pi supplementation at concentrations equivalent to and twice as much as that in the control diet was performed. The localized PVAT inflammation was reversed in a dose-dependent manner. The increased expression of UCP1 (uncoupling protein1), HIF-1α (hypoxia inducible factor-1α), and IL-1β (interleukin-1β), representing the hallmark of PVAT inflammation in this rat model, were reversed, with normalization of PVAT macrophage polarization. Pi supplementation restored the metabolic efficiency consistent with its putative role as an UCP1 inhibitor. Alongside, parasympathetic autonomic and cerebrovascular dysfunction function observed in the prediabetic model was reversed, together with the mitigation of multiple molecular and histological cardiovascular damage markers. Significantly, a Pi-deficient control diet neither induced PVAT inflammation nor cardiovascular dysfunction, whereas Pi reinstatement in the diet after a 10-week exposure to a hypercaloric low-Pi diet ameliorated the dysfunction. Conclusions Our present results propose Pi supplementation as a simple intervention to reverse PVAT inflammation and its early cardiovascular consequences, possibly through the interference with hypercaloric-induced increase in UCP1 expression/activity.
    Keywords:  inorganic phosphorous; perivascular adipose inflammation; prediabetes; uncoupling protein 1
  14. Int Immunopharmacol. 2021 Dec 07. pii: S1567-5769(21)01049-3. [Epub ahead of print]102 108413
      OBJECT: Atherosclerosis (AS) is caused by chronic inflammation. Artesunate (ART), a sesquiterpene lactone endoperoxide isolated from Chinese herbal medicine, displays excellent anti-inflammatory activity. In this study, we investigated the effects of artesunate on atherosclerosis in ApoE knock-out mice, and used untargeted metabolomics to determine metabolite changes in these mice following ART treatment.METHODS: ApoE knock-out mice were fed a western diet and administered ART for eight weeks. Untargeted metabolomics was used to detect differential metabolites following the administration of ART. Oil Red O was used to assess plaque size, western blot and ELISA were used to detect inflammatory factors, and flow cytometry was used to detect the expression of markers on macrophages.
    RESULTS: Results of the in vivo experiment suggested that ART reduced atherosclerotic plaques in murine aortic root. In addition both in vivo and vitro experiments suggested that ART reduced the expression levels of inflammating cytokines, but enhanced those of the anti-inflammatory cytokines in macrophages. Untargeted metabolomic analysis demonstrated that multiple metabolic pathways, which were blocked in AS mice, showed different degrees of improvement following ART treatment. Furthermore, bioinformatic analyses showed that the HIF-1α pathway was altered in the AS mice and the ART treatment mice. In vitro experiments confirmed that LPS-induced upregulation of HIF-1α expression and activation of the NF-κB signaling pathways was significantly inhibited by ART treatment.
    CONCLUSION: These results suggest that ART exerts anti-atherosclerosis effects by inhibiting M1 macrophage polarization. One of the molecular mechanisms is that ART inhibits M1-like macrophage polarization via regulating HIF-1α and NF-κB signaling pathways.
    Keywords:  Artesunate; Atherosclerosis; HIF-1α; Inflammation; Macrophages polarization
  15. Eur J Immunol. 2021 Dec 06.
      To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2 we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function, including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies. This article is protected by copyright. All rights reserved.
    Keywords:  COVID-19; glycolysis; metabolism; neutrophil extracellular traps; neutrophils
  16. Cell Metab. 2021 Dec 07. pii: S1550-4131(21)00537-4. [Epub ahead of print]33(12): 2305-2306
      The metabolic state of T cells strongly influences their effector function and anti-tumor efficacy. St. Paul et al. (2021) report that Tc22, a CD8+ T cell subset with potent anti-tumor activity, upregulates the pantothenate/coenzyme A (CoA) pathway and that treatment with CoA or pantothenate is sufficient to enhance tumor immunotherapy.
  17. Surgery. 2021 Dec 04. pii: S0039-6060(21)01094-1. [Epub ahead of print]
      BACKGROUND: Along with the rising incidence of obesity, there has been an increase in patients diagnosed with early-onset colorectal cancer (<50 years old). In colorectal cancer, worse patient survival is associated with certain cytokine expression and downregulation of peroxisome proliferator activated receptor gamma expression. The effects of the obesity hormone leptin and macrophage-specific metabolite itaconate on these mechanisms are poorly understood. We investigated their impact on peroxisome proliferator activated receptor gamma and macrophage cytokine expression in vitro.METHODS: M2-like macrophages were treated with either leptin, 4-octyl itaconate, or dimethyl itaconate in a dose- and time-dependent manner. Gene expression after treatment with 4 doses (D1-4) of each compound was analyzed at 4 time points (3, 6, 18, and 24 hours).
    RESULTS: Peroxisome proliferator activated receptor gamma was downregulated after 4-octyl itaconate treatment at 18 hours (FC -32.67, P ≤ .001). Interleukin-8 was upregulated after leptin and dimethyl itaconate treatment at 6 hours (FC 26.35 at D4, P ≤ .001, and FC 23.26 at D3, P = .006). Dimethyl itaconate upregulated IL-1β at 24 hours (FC 18.00 at D4, P ≤ .001). Tumor necrosis factor-α showed maximum downregulation after 4-octyl itaconate at 18 hours (FC -103.25 at D4, P ≤ .001).
    CONCLUSIONS: Itaconate downregulates peroxisome proliferator activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Itaconate provides a link between obesity and colorectal cancer and may be a key regulator in early-onset colorectal cancer.
  18. J Immunol. 2021 Dec 06. pii: ji2100452. [Epub ahead of print]
      CD8+ memory T (TM) cells play a critical role in immune defense against infection. Two common γ-chain family cytokines, IL-2 and IL-7, although triggering the same mTORC1-S6K pathway, distinctly induce effector T (TE) cells and TM cells, respectively, but the underlying mechanism(s) remains elusive. In this study, we generated IL-7R-/and AMPKα1-knockout (KO)/OTI mice. By using genetic and pharmaceutical tools, we demonstrate that IL-7 deficiency represses expression of FOXO1, TCF1, p-AMPKα1 (T172), and p-ULK1 (S555) and abolishes T cell memory differentiation in IL-7R KO T cells after Listeria monocytogenesis rLmOVA infection. IL-2- and IL-7-stimulated strong and weak S6K (IL-2/S6Kstrong and IL-7/S6Kweak) signals control short-lived IL-7R-CD62L-KLRG1+ TE and long-term IL-7R+CD62L+KLRG1- TM cell formations, respectively. To assess underlying molecular pathway(s), we performed flow cytometry, Western blotting, confocal microscopy, and Seahorse assay analyses by using the IL-7/S6Kweak-stimulated TM (IL-7/TM) and the control IL-2/S6Kstrong-stimulated TE (IL-2/TE) cells. We determine that the IL-7/S6Kweak signal activates transcriptional FOXO1, TCF1, and Id3 and metabolic p-AMPKα1, p-ULK1, and ATG7 molecules in IL-7/TM cells. IL-7/TM cells upregulate IL-7R and CD62L, promote mitochondria biogenesis and fatty acid oxidation metabolism, and show long-term cell survival and functional recall responses. Interestingly, AMPKα1 deficiency abolishes the AMPKα1 but maintains the FOXO1 pathway and induces a metabolic switch from fatty acid oxidation to glycolysis in AMPKα1 KO IL-7/TM cells, leading to loss of cell survival and recall responses. Taken together, our data demonstrate that IL-7-stimulated weak strength of mTORC1-S6K signaling controls T cell memory via activation of transcriptional FOXO1-TCF1-Id3 and metabolic AMPKα1-ULK1-ATG7 pathways. This (to our knowledge) novel finding provides a new mechanism for a distinct IL-2/IL-7 stimulation model in T cell memory and greatly impacts vaccine development.
  19. EBioMedicine. 2021 Dec 04. pii: S2352-3964(21)00528-4. [Epub ahead of print]74 103734
      BACKGROUND: L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine.METHODS: L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using [13C] glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice.
    FINDINGS: We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, [13C]-tracing revealed that co-stimulated CD4+ T cells exposed to L-/D-kynurenine undergo increased β-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 μM, which is close to human kidney (6 μM) and head and neck cancer (14 μM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1-/- mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection.
    INTERPRETATION: Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials.
    FUNDING: The study was supported by the NIH, the Else Kröner-Fresenius-Foundation, Laffey McHugh foundation, and American Society of Nephrology.
    Keywords:  T cell metabolism; aryl hydrocarbon receptor; cancer metabolism; immunosuppression; indoleamine-2,3-dioxygenase; tumour microenvironment
  20. Biomed Chromatogr. 2021 Dec 10. e5297
      Atherosclerosis (AS) is associated with increasing lipid peroxidation, oxidative modification LDL (ox-LDL) is one most important factor contributing to the pathogenesis and clinical feature of AS. The lipid composition influenced by ox-LDL is not known clearly. In this work, UHPLC/Orbitrap MS-based lipidomics approach integrated pathway analysis was performed to advance the understanding of the lipid composition and feature pathway in ox-LDL induced foamy macrophage cell. In the lipid metabolic profiling, 196 lipid species from 15 (sub) classes were identified. Lipid profiling indicated overtaking ox-LDL caused lipid metabolic alternations, manifesting as phospholipids down-regulated and sphingolipids up-regulated. Pathway analysis explored glycerophospholipid and sphingolipid metabolism were mainly involved in atherogenic changes. Notably, dysregulated ceramide metabolism was the typical feature of foamy cell formation. qRT-PCR analysis was conducted to explore the differentially expressed gene. It indicated that ceramide metabolic balance might be a mainly disordered, performing higher synthesis and lower hydrolysis, with the ratio of SMPD1/SGMS2 up-regulated significantly (p<0.05) in ox-LDL induced group. Our work offers a comprehensive understanding of macrophage-derived foam cells and screen feature pathways associated with foamy cell formation, which provides a reference for the clinic diagnosis and drug intervention of AS.
    Keywords:  atherosclerosis; ceramide metabolism; drug discovery; foamy macrophages; lipidomics
  21. Nat Commun. 2021 Dec 08. 12(1): 7130
      Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Using mouse models, we show that inducible CD36 is required for free fatty acid uptake by HSCs during acute infection, allowing the metabolic transition from glycolysis towards β-oxidation. Mechanistically, high CD36 levels promote FFA uptake, which enables CPT1A to transport fatty acyl chains from the cytosol into the mitochondria. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection. These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge.