bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒05‒29
thirty-two papers selected by
Dylan Ryan
University of Cambridge

  1. Sci Immunol. 2022 May 27. 7(71): eabh4271
      Memory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their capacity to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting their rapid recall response are incompletely understood. Here, we identify a role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously activated CD8+ T cells. We found that CAD was rapidly phosphorylated upon naïve T cell activation in an mTORC1-dependent manner, yet remained phosphorylated long after initial activation. Previously activated CD8+ T cells displayed continued de novo pyrimidine synthesis in the absence of mitogenic signals, and interfering with this pathway diminished the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD did not affect cytokine transcript levels but diminished available pre-rRNA (ribosomal RNA), the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreased levels of detectable ribosomal proteins in previously activated CD8+ T cells. Conversely, overexpression of CAD improved both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells.
  2. Sci Adv. 2022 May 27. 8(21): eabm9120
      Cellular metabolism has been proposed to govern distinct γδ T cell effector functions, but the underlying molecular mechanisms remain unclear. We show that interleukin-17 (IL-17)-producing γδ T (γδT17) and interferon-γ (IFN-γ)-producing γδ T (γδT1) cells have differential metabolic requirements and that the rate-limiting enzyme isocitrate dehydrogenase 2 (IDH2) acts as a metabolic checkpoint for their effector functions. Intriguingly, the transcription factor c-Maf regulates γδT17 effector function through direct regulation of IDH2 promoter activity. Moreover, mTORC2 affects the expression of c-Maf and IDH2 and subsequent IL-17 production in γδ T cells. Deletion of c-Maf in γδ T cells reduces metastatic lung cancer development, suggesting c-Maf as a potential target for cancer immune therapy. We show that c-Maf also controls IL-17 production in human γδ T cells from peripheral blood and in oral cancers. These results demonstrate a critical role of the transcription factor c-Maf in regulating γδT17 effector function through IDH2-mediated metabolic reprogramming.
  3. Nat Metab. 2022 May 23.
      Regulatory T (Treg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Treg cells causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced α-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient Treg cells. We also find that TKT levels are frequently downregulated in Treg cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.
  4. Nat Metab. 2022 May 26.
      Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs Treg survival starting in young mice and reduces Treg homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible Treg cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As Treg homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.
  5. Front Immunol. 2022 ;13 869197
      Cellular metabolic remodeling is intrinsically linked to the development, activation, differentiation, function, and survival of T cells. T cells transition from a catabolic, naïve state to an anabolic effector state upon T cell activation. Subsequently, specialization of T cells into T helper (Th) subsets, including regulatory T cells (Treg), requires fine-tuning of metabolic programs that better support and optimize T cell functions for that particular environment. Increasingly, studies have shown that changes in nutrient availability at both the cellular and organismal level during disease states can alter T cell function, highlighting the importance of better characterizing metabolic-immune axes in both physiological and disease settings. In support of these data, a growing body of evidence is emerging that shows specific lipid species are capable of altering the inflammatory functional phenotypes of T cells. In this review we summarize the metabolic programs shown to support naïve and effector T cells, and those driving Th subsets. We then discuss changes to lipid profiles in patients with multiple sclerosis, and focus on how the presence of specific lipid species can alter cellular metabolism and function of T cells.
    Keywords:  T cell; T regulatory (Treg) cell; fatty acids; immunometabolism; multiple sclerosis
  6. Cell. 2022 May 13. pii: S0092-8674(22)00530-X. [Epub ahead of print]
      2',3'-cAMP is a positional isomer of the well-established second messenger 3',5'-cAMP, but little is known about the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have the NADase function necessary but insufficient to activate plant immune responses. Here, we show that plant TIR proteins, besides being NADases, act as 2',3'-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data show that a TIR domain adopts distinct oligomers with mutually exclusive NADase and synthetase activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana (Nb), supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7, displays 2',3'-cAMP/cGMP but not 3',5'-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in Nb. Our study identifies a family of 2',3'-cAMP/cGMP synthetases and establishes a critical role for them in plant immune responses.
    Keywords:  2′,3′-cAMP/cGMP phosphodiesterases; 2′,3′-cAMP/cGMP synthetases; NLRs; TIRs; bifunctional enzymes; plant immunity
  7. Biochim Biophys Acta Mol Basis Dis. 2022 May 23. pii: S0925-4439(22)00122-3. [Epub ahead of print] 166452
      CD226 is a costimulatory molecule that regulates immune cell functions in T cells, natural killer cells, and macrophages. Because macrophage-derived foam cell formation is a crucial factor contributing to the development of atherosclerosis, we aimed to evaluate the potential roles of CD226 in the pathogenesis of atherosclerosis. The effects of CD226 on atherosclerosis were investigated in CD226 and apolipoprotein E double-knockout (CD226-/- ApoE-/-) mice fed with a high-cholesterol atherogenic diet. CD226 expression in macrophages was evaluated using flow cytometry. Histopathological analysis was performed to evaluate the atherosclerotic lesions. Inflammatory cell infiltration was detected using immunofluorescence staining. Bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PEMs) were isolated from the mice and used to explore the mechanism in vitro. The in vivo results indicated that CD226 knockdown protected against atherosclerosis in ApoE-/- mice, evidenced by reduced plaque accumulation in the brachiocephalic artery, aortic roots, and main aortic tree. CD226 gene-deficient macrophages showed reduced foam cell formation under ox-low density lipoprotein stimulation compared with wild-type (WT) cells. CD226 deficiency also decreased the expression of CD36 and scavenger receptor (SR)-A (responsible for lipoprotein uptake) but increased the expression of ATP-binding cassette transporter A1 and G1 (two transporters for cholesterol efflux). Therefore, loss of CD226 hinders foam cell formation and atherosclerosis progression, suggesting that CD226 is a promising new therapeutic target for atherosclerosis.
    Keywords:  Atherosclerosis; CD226 gene knockout mice; Foam cell formation; Lipid metabolism
  8. Int J Cancer. 2022 May 27.
      Oncolytic viruses (OVs) represent a class of cancer immunotherapies that rely on hijacking the host cell factory for replicative oncolysis and eliciting immune responses for tumor clearance. An increasing evidence suggests that the metabolic state of tumor cells and immune cells is a putative determinant of the efficacy of cancer immunotherapy. However, how therapeutic intervention with OVs affects metabolic fluxes within the tumor microenvironment (TME) remains poorly understood. Herein, we review the complexities of metabolic reprogramming involving the effects of viruses and their consequences on tumor cells and immune cells. We highlight the inherent drawback of oncolytic virotherapy, namely that treatment with OVs inevitably further exacerbates the depletion of nutrients and the accumulation of metabolic wastes in the TME, leading to a metabolic barrier to antitumor immune responses. We also describe targeted metabolic strategies that can be used to unlock the therapeutic potential of OVs.
    Keywords:  immunotherapy; metabolic reprogramming; oncolytic virus; tumor microenvironment
  9. Genes (Basel). 2022 Apr 25. pii: 756. [Epub ahead of print]13(5):
      The implication of the heterogeneous spectrum of pro- and anti-inflammatory macrophages (Macs) has been an important area of investigation over the last decade. The polarization of Macs alters their functional phenotype in response to their surrounding microenvironment. Macs are the major immune cells implicated in the pathogenesis of atherosclerosis. A hallmark pathology of atherosclerosis is the accumulation of pro-inflammatory M1-like macrophages in coronary arteries induced by pro-atherogenic stimuli; these M1-like pro-inflammatory macrophages are incapable of digesting lipids, thus resulting in foam cell formation in the atherosclerotic plaques. Recent findings suggest that the progression and stability of atherosclerotic plaques are dependent on the quantity of infiltrated Macs, the polarization state of the Macs, and the ratios of different types of Mac populations. The polarization of Macs is defined by signature markers on the cell surface, as well as by factors in intracellular and intranuclear compartments. At the same time, pro- and anti-inflammatory polarized Macs also exhibit different gene expression patterns, with differential cellular characteristics in oxidative phosphorylation and glycolysis. Macs are reflective of different metabolic states and various types of diseases. In this review, we discuss the major differences between M1-like Macs and M2-like Macs, their associated metabolic pathways, and their roles in atherosclerosis.
    Keywords:  atherosclerosis; immunometabolism; innate immunity; macrophage; polarization
  10. Sci Rep. 2022 May 25. 12(1): 8807
      Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct anti-inflammatory effect and anti-atherogenic effects of PNLA on activated purified CD14 monocytes from peripheral blood of patients with rheumatoid arthritis (RA) in vitro. Flow cytometry was used to assess the proportions of CD14 monocytes expressing TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptome (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing. PNLA reduced percentage of monocytes expressing cytokines: TNF-α by 23% (p = 0.048), IL-6 by 25% (p = 0.011), IL-1β by 23% (p = 0.050), IL-8 by 20% (p = 0.066). Pathway analysis identified upstream activation of peroxisome proliferator-activated receptors (PPARs), sirtuin3, and let7 miRNA, and KLF15, which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-α, and IL-6 signal transduction, were inhibited. Canonical Pathway analysis showed that PNLA inhibited oxidative phosphorylation (p = 9.14E-09) and mitochondrial dysfunction (p = 4.18E-08), while the sirtuin (SIRTs) signalling pathway was activated (p = 8.89E-06) which interfere with the pathophysiological process of atherosclerosis. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and acetyl-CoA acyltranferase2 (ACAA2); genes implicated in regulation of lipid and cell metabolism, inflammation, and mitochondrial dysfunction. PNLA has potential anti-atherogenic and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation regulates key miRNAs that are involved in metabolic, mitochondrial, and inflammatory pathways.
  11. Cells. 2022 May 17. pii: 1663. [Epub ahead of print]11(10):
      Immune cells undergo different metabolic pathways or immunometabolisms to interact with various antigens. Immunometabolism links immunological and metabolic processes and is critical for innate and adaptive immunity. Although metabolic reprogramming is necessary for cell differentiation and proliferation, it may mediate the imbalance of immune homeostasis, leading to the pathogenesis and development of some diseases, such as autoimmune diseases. Here, we discuss the effects of metabolic changes in autoimmune diseases, exerted by the leading actors of innate immunity, and their role in autoimmunity pathogenesis, suggesting many immunotherapeutic approaches.
    Keywords:  HIF-1α; autoimmunity; chronic inflammatory disease; glycolysis; immune response; innate immunity; metabolic pathways; oxidative phosphorylation; therapy
  12. Biochimie. 2022 May 23. pii: S0300-9084(22)00133-X. [Epub ahead of print]
      The unregulated uptake of modified low-density lipoproteins (LDL) by macrophages leads to foam cell formation, promoting atherosclerotic plaque progression. The cholesterol efflux capacity of macrophages by the ATP-Binding Cassette transporters depends on the ATP mitochondrial production. Therefore, the mitochondrial function maintenance is crucial in limiting foam cell formation. Thus, we aimed to investigate the mechanisms involved in the mitochondrial dysfunction that may occur in cholesterol-laden macrophages. We incubated THP-1 macrophages with acetylated LDL (acLDL) to obtain cholesterol-laden cells or with mildly oxidized LDL (oxLDL) to generate cholesterol- and oxidized lipids-laden cells. Cellular cholesterol content was measured in each condition. Mitochondrial function was evaluated by measurement of several markers of energetic metabolism, oxidative phosphorylation, oxidative stress, mitochondrial biogenesis and dynamics. OxLDL-exposed macrophages exhibited a significantly reduced mitochondrial respiration and complexes I and III activities, associated to an oxidative stress state and a reduced mitochondrial DNA copy number. Meanwhile, acLDL-exposed macrophages featured an efficient oxidative phosphorylation despite the decreased activities of aconitase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Our study revealed that mitochondrial function was differently impacted according to the nature of modified LDL. Exposure to cholesterol and oxidized lipids carried by oxLDL leads to a mitochondrial dysfunction in macrophages, affecting the mitochondrial respiratory chain functional capacity, whereas the cellular cholesterol enrichment induced by acLDL exposure results in a tricarboxylic acid cycle shunt while maintaining mitochondrial energetic production, reflecting a metabolic adaptation to cholesterol intake. These new mechanistic insights are of direct relevance to the understanding of the mitochondrial dysfunction in foam cells.
    Keywords:  Atherosclerosis; Cholesterol; Foam cells; Low-density lipoprotein; Macrophage; Mitochondrion; Oxidative stress; Respiratory chain
  13. STAR Protoc. 2022 Jun 17. 3(2): 101389
      Metabolic reprogramming is associated with myeloid-derived suppressor cell (MDSC) immunosuppressive function. Here, we outline the process for acquiring MDSCs from human and murine sources for subsequent analysis of fatty acid oxidation, oxidative phosphorylation, and glycolysis using the Seahorse XFe 96 Analyzer. Murine MDSCs can be isolated directly from tumor-bearing mice or derived through IL-6 and GM-CSF culture of bone marrow cells from non-tumor-bearing mice. To generate human MDSCs, peripheral blood mononuclear cells (PBMCs) can be cultured with IL-6 and GM-CSF. For complete details on the use and execution of this protocol, please refer to Mohammadpour et al. (2021).
    Keywords:  Cancer; Cell Biology; Cell isolation; Cell-based Assays; Immunology; Metabolism; Model Organisms
  14. J Neuroimmunol. 2022 May 19. pii: S0165-5728(22)00088-1. [Epub ahead of print]368 577893
      Mitochondria-mediated metabolic impairment and dysfunction are highly related with autism. Herein, the mitochondria-mediated metabolism of BTBR T+Itpr3tf/J (BTBR) mice with autistic-like behaviors was investigated. A new BTBR-mtB6 strain generated by deriving BTBR mice with C57BL/6J (B6) mitochondria was used to determine the role of the mitochondrial genome. The BTBR-mtB6 mice had improved social behaviors, higher levels of glutamate and astrocytes in the brain and less neuroinflammation than the BTBR mice; however, many of the metabolic parameters of BTBR mice such as enhanced fatty acid β-oxidation and lower glycolysis and glutaminolysis in immune cells compared to B6 mice were not or only partial improved in the BTBR-mtB6 strain. The BTBR and BTBR-mtB6 mice also had equivalent ETC (enhanced electron transport chain) activity of mitochondria, with an increase of reactive oxygen species (ROS) and decreased mitochondrial membrane potential compared to the B6 mice. The results suggest that the mitochondrial replacement with its metabolic alterations affect brain functions more than peripheral immune cell activities.
    Keywords:  Autism; Electron transport chain; Metabolic switch; Mitochondrial dysfunction; Mitochondrial membrane potential; Neuroinflammation; Oxidative stress; Social behavior
  15. J Formos Med Assoc. 2022 May 19. pii: S0929-6646(22)00188-7. [Epub ahead of print]
      BACKGROUND/PURPOSE: Recent emerging evidence indicates that dysfunction of metabolic remodeling underlies aberrant T cell immune responses in systemic lupus erythematosus (SLE). This study was undertaken to investigate the expression of HIF-1α, a regulator of metabolic reprogramming, in T cells from SLE.METHODS: HIF-1α expression in T lymphocytes from SLE patients was examined by quantitative polymerase chain reaction (PCR) and the protein expression was analyzed with intracellular staining in flow cytometry. HIF-1α was overexpressed in murine CD4 T cells via transducing T cells with HIF-1α containing lentivirus. The expression of HIF-1α, metabolic- and Th17-associated genes in T cells from SLE patients and its association with clinical manifestation was analyzed.
    RESULTS: HIF-1α expression is increased in CD4 T cells from SLE patients both in intracellular staining and quantitative PCR analysis. In addition, there is enhanced HIF-1α expression in Th17-skewing murine T cells, and lentivirus-mediated HIF-1α overexpression promotes Th17 differentiation. Moreover, HIF-1α gene expression is positively correlated with the expression of glycolysis- and IL-17-associated genes in SLE patients.
    CONCLUSION: HIF-1α expression is increased in T cells from SLE patients, and is positively correlated with glycolysis- and Th17- associated pathway, implicating HIF-1α contributes to the activation of Th17 cells in SLE, and represents a potential novel therapeutic target.
    Keywords:  CD4 T cells; HIF-1α; Metabolic reprogramming; SLE; Th17
  16. STAR Protoc. 2022 Jun 17. 3(2): 101408
      Metabolism is important for the regulation of hematopoietic stem cells (HSCs) and drives cellular fate. Due to the scarcity of HSCs, it has been technically challenging to perform metabolome analyses gaining insight into HSC metabolic regulatory networks. Here, we present two targeted liquid chromatography-mass spectrometry approaches that enable the detection of metabolites after fluorescence-activated cell sorting when sample amounts are limited. One protocol covers signaling lipids and retinoids, while the second detects tricarboxylic acid cycle metabolites and amino acids. For complete details on the use and execution of this protocol, please refer to Schönberger et al. (2022).
    Keywords:  Mass Spectrometry; Metabolomics; Stem Cells
  17. Nat Commun. 2022 May 26. 13(1): 2950
      Within adipose tissue (AT), immune cells and parenchymal cells closely interact creating a complex microenvironment. In obesity, immune cell derived inflammation contributes to insulin resistance and glucose intolerance. Diet-induced weight loss improves glucose tolerance; however, weight regain further exacerbates the impairment in glucose homeostasis observed with obesity. To interrogate the immunometabolic adaptations that occur in AT during murine weight loss and weight regain, we utilized cellular indexing of transcriptomes and epitopes by sequencing (CITEseq) in male mice. Obesity-induced imprinting of AT immune cells persisted through weight-loss and progressively worsened with weight regain, ultimately leading to impaired recovery of type 2 regulatory cells, activation of antigen presenting cells, T cell exhaustion, and enhanced lipid handling in macrophages in weight cycled mice. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. For further discovery, we provide an open-access web portal of diet-induced AT immune cell imprinting: .
  18. Biomedicines. 2022 May 17. pii: 1152. [Epub ahead of print]10(5):
      BACKGROUND: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells.METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells.
    CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.
    Keywords:  cholesterol; dendritic cells; interferon; nuclear receptor; toll like receptors; viral response
  19. Biomolecules. 2022 May 18. pii: 716. [Epub ahead of print]12(5):
      Although the discovery of immune checkpoints was hailed as a major breakthrough in cancer therapy, generating a sufficient response to immunotherapy is still limited. Thus, the objective of this exploratory, hypothesis-generating study was to identify potentially novel peripheral biomarkers and discuss the possible predictive relevance of combining scarcely investigated metabolic and hormonal markers with immune subsets. Sixteen markers that differed significantly between responders and non-responders were identified. In a further step, the correlation with progression-free survival (PFS) and false discovery correction (Benjamini and Hochberg) revealed potential predictive roles for the immune subset absolute lymphocyte count (rs = 0.51; p = 0.0224 *), absolute basophil count (rs = 0.43; p = 0.04 *), PD-1+ monocytes (rs = -0.49; p = 0.04 *), hemoglobin (rs = 0.44; p = 0.04 *), metabolic markers LDL (rs = 0.53; p = 0.0224 *), free androgen index (rs = 0.57; p = 0.0224 *) and CRP (rs = -0.46; p = 0.0352 *). The absolute lymphocyte count, LDL and free androgen index were the most significant individual markers, and combining the immune subsets with the metabolic markers into a biomarker ratio enhanced correlation with PFS (rs = -0.74; p ≤ 0.0001 ****). In summary, in addition to well-established markers, we identified PD-1+ monocytes and the free androgen index as potentially novel peripheral markers in the context of immunotherapy. Furthermore, the combination of immune subsets with metabolic and hormonal markers may have the potential to enhance the power of future predictive scores and should, therefore, be investigated further in larger trials.
    Keywords:  PD-1; PD-1+ monocytes; cholesterol; free androgen index; hemoglobin; hormones; immune cells; immunotherapy; metabolism; testosterone
  20. Thorax. 2022 May 25. pii: thoraxjnl-2021-218047. [Epub ahead of print]
      RATIONALE: The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.OBJECTIVE: To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.
    METHODS: We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients.
    RESULTS: Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction.
    CONCLUSION: These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.
    Keywords:  Bacterial Infection; Critical Care; Emergency Medicine; Pneumonia
  21. Viruses. 2022 May 06. pii: 983. [Epub ahead of print]14(5):
      Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.
    Keywords:  RAGE; SARS-CoV-2; Tepp-46; glycolysis; inflammation; metabolic reprogramming; mitochondria
  22. Oxid Med Cell Longev. 2022 ;2022 5216786
      Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.
  23. J Leukoc Biol. 2022 May 23.
      Type 2 immune responses are mediated by the cytokines interleukin (IL)-4, IL-5, IL-10, and IL-13 and associated cell types, including T helper (Th)2 cells, group 2 innate lymphoid cells (ILC2s), basophils, mast cells, eosinophils, and IL-4- and IL-13-activated macrophages. It can suppress type 1-driven autoimmune diseases, promote antihelminth immunity, maintain cellular metabolic homeostasis, and modulate tissue repair pathways following injury. However, when type 2 immune responses become dysregulated, they can be a significant pathogenesis of many allergic and fibrotic diseases. As such, there is an intense interest in studying the pathways that modulate type 2 immune response so as to identify strategies of targeting and controlling these responses for tissue healing. Herein, we review recent literature on the metabolic regulation of immune cells initiating type 2 immunity and immune cells involved in the effector phase, and talk about how metabolic regulation of immune cell subsets contribute to tissue repair. At last, we discuss whether these findings can provide a novel prospect for regenerative medicine.
    Keywords:  immune cell; immunomodulation; metabolic regulation; tissue repair; type 2 immunity
  24. Mol Cell. 2022 May 05. pii: S1097-2765(22)00327-6. [Epub ahead of print]
      Activated CD8+ T lymphocytes differentiate into heterogeneous subsets. Using super-resolution imaging, we found that prior to the first division, dynein-dependent vesicular transport polarized active TORC1 toward the microtubule-organizing center (MTOC) at the proximal pole. This active TORC1 was physically associated with active eIF4F, required for the translation of c-myc mRNA. As a consequence, c-myc-translating polysomes polarized toward the cellular pole proximal to the immune synapse, resulting in localized c-myc translation. Upon division, the TORC1-eIF4A complex preferentially sorted to the proximal daughter cell, facilitating asymmetric c-Myc synthesis. Transient disruption of eIF4A activity at first division skewed long-term cell fate trajectories to memory-like function. Using a genetic barcoding approach, we found that first-division sister cells often displayed differences in transcriptional profiles that largely correlated with c-Myc and TORC1 target genes. Our findings provide mechanistic insights as to how distinct T cell fate trajectories can be established during the first division.
    Keywords:  CD8(+) T cells; STED; STORM; asymmetric cell division; c-Myc; cell fate; eIF4A; polarization; scRNA-seq; translation
  25. Cell Rep. 2022 May 24. pii: S2211-1247(22)00620-9. [Epub ahead of print]39(8): 110847
      Tissue damage leads to loss of cellular and mitochondrial membrane integrity and release of damage-associated molecular patterns, including those of mitochondrial origin (mitoDAMPs). Here, we describe the lymphocyte response to mitoDAMPs. Using primary cells from mice and human donors, we demonstrate that natural killer (NK) cells and T cells adopt regulatory phenotypes and functions in response to mitoDAMPs. NK cell-mediated cytotoxicity, interferon gamma (IFN-γ) production, T cell proliferation, and in vivo anti-viral T cell activation are all interrupted in the presence of mitoDAMPs or mitoDAMP-rich irradiated cells in in vitro and in vivo assays. Mass spectrometry analysis of mitoDAMPs demonstrates that arginase and products of its enzymatic activity are prevalent in mitoDAMP preparations. Functional validation by arginase inhibition and/or arginine add-back shows that arginine depletion is responsible for the alteration in immunologic polarity. We conclude that lymphocyte responses to mitoDAMPs reflect a highly conserved mechanism that regulates inflammation in response to tissue injury.
    Keywords:  CP: Immunology; NK cell; arginase; arginine metabolism; damage-associated molecular patterns (DAMPs); immunoregulation; lymphocytes; mass spectrometry; mitochondria; natural killer cell; tissue damage
  26. Cells. 2022 May 23. pii: 1718. [Epub ahead of print]11(10):
      Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca2+-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization.
    Keywords:  SMOC1; macrophage polarization; thrombin
  27. Aging Cell. 2022 May 22. e13622
      Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP-AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN-induced kinase 1 (PINK1)/Parkin-mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin-1 treatment. Consequently, Pink1 overexpression in combination with Torin-1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR-induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.
    Keywords:  aging; macrophage; mitochondrial DNA; mitophagy; sterile inflammation; stimulator of interferon genes
  28. Amino Acids. 2022 May 23.
      Behçet disease (BD) is an inflammatory, multisystemic vasculitis of unknown etiopathogenesis. However, innate and adaptive immune system involvement and immune-mediated networks play a vital role in the inflammatory cascade. Indoleamine 2,3-dioxygenase 1 (IDO1) is activated in chronic inflammatory states and catalyzes the first and rate-limiting step of tryptophan (TRP) metabolism along the kynurenine pathway (KP). The study aimed to measure KP metabolites levels in patients with BD and investigate the relationship between disease activity and clinical findings with these metabolites. The study included 120 patients with BD and 120 healthy volunteers. Serum TRP, kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), and quinolinic acid (QUIN) levels were measured with the tandem mass spectrometric method. Demographic data, clinical manifestations, and disease activity score (BDCAF) were recorded. Serum KYN, KYNA, 3HK, 3HAA, QUIN levels, and KYN/TRP ratio were higher (p < 0.05) in patients with BD compared to the control group, while TRP levels were lower (p < 0.05). KYN/TRP ratio and QUIN levels were significantly higher in the presence of neuro-Behçet, while serum KYN levels were significantly higher in the presence of arthritis (p < 0.05). In addition, serum QUIN levels were significantly higher in the presence of thrombosis (p < 0.05). BDCAF score positively correlated with KYN/TRP ratio. Our findings showed that serum KP metabolite levels were elevated in patients with BD, and there is a relationship between these metabolites with disease activity, clinical findings, and inflammatory burden.
    Keywords:  Behçet disease; Immune regulation; Inflammation; Kynurenine pathway
  29. Pathogens. 2022 May 03. pii: 537. [Epub ahead of print]11(5):
      Interferons (IFNs) are an essential part of innate immunity and contribute to adaptive immune responses. Here, we employed a loss-of-function analysis with human A549 respiratory epithelial cells with a knockout (KO) of the type I IFN receptor (IFNAR KO), either solely or together with the receptor of type III IFN (IFNAR/IFNLR1 KO). The course of rubella virus (RuV) infection on the IFNAR KO A549 cells was comparable to the control A549. However, on the IFNAR/IFNLR1 KO A549 cells, both genome replication and the synthesis of viral proteins were significantly enhanced. The generation of IFN β during RuV infection was influenced by type III IFN signaling. In contrast to IFNAR KO A549, extracellular IFN β was not detected on IFNAR/IFNLR1 KO A549. The bioenergetic profile of RuV-infected IFNAR/IFNLR1 KO A549 cells generated by extracellular flux analysis revealed a significant increase in glycolysis, whereas mitochondrial respiration was comparable between all three cell types. Moreover, the application of the glucose analogue 2-deoxy-D-glucose (2-DG) significantly increased viral protein synthesis in control A549 cells, while no effect was noted on IFNAR/IFNLR KO A549. In conclusion, we identified a positive signaling circuit of type III IFN signaling on the generation of IFN β during RuV infection and an IFN signaling-dependent contribution of glycolysis to RuV infection. This study on epithelial A549 cells emphasizes the interaction between glycolysis and antiviral IFN signaling and notably, the antiviral activity of type III IFNs against RuV infection, especially in the absence of both type I and III IFN signaling, the RuV replication cycle was enhanced.
    Keywords:  2-deoxy-D-glucose; extracellular acidification rate; extracellular flux analysis; glycolysis; oxygen consumption rate
  30. Blood Adv. 2022 May 27. pii: bloodadvances.2022007033. [Epub ahead of print]
      Rapid and effective leucocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the bone marrow niche on this phenotype. We found that, in response to LPS induced stress, HPC mitochondrial function is impaired and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared to young animals. Furthermore, aged mesenchymal stromal cells (MSC) of the BM niche, but not HPCs, exhibit a senescent phenotype and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with LPS. In summary, age related HPC metabolic dysfunction occurs indirectly as a 'bystander phenomenon' in the aging BM niche and can be restored by targeting senescent MSCs.