bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒06‒05
25 papers selected by
Dylan Ryan
University of Cambridge

  1. J Clin Invest. 2022 Jun 02. pii: e160852. [Epub ahead of print]
      Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with down-regulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a novel metabolic immune checkpoint.
    Keywords:  Autoimmune diseases; Immunology; Immunotherapy; Metabolism; T cell development
  2. Nat Metab. 2022 Jun 02.
      Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor.
  3. Nat Metab. 2022 Jun 02.
      Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.
  4. Front Immunol. 2022 ;13 839390
      CD4+ T cell differentiation to pro-inflammatory and immunosuppressive subsets depends on immunometabolism. Pro-inflammatory CD4+ subsets rely on glycolysis, while immunosuppressive Treg cells require functional mitochondria for their differentiation and function. Previous pre-clinical studies have shown that ethanol (EtOH) administration increases pro-inflammatory CD4+ T cell subsets; whether this shift in immunophenotype is linked to alterations in CD4+ T cell metabolism had not been previously examined. The objective of this study was to determine whether ethanol alters CD4+ immunometabolism, and whether this affects CD4+ T cell differentiation. Naïve human CD4+ T cells were plated on anti-CD3 coated plates with soluble anti-CD28, and differentiated with IL-12 in the presence of ethanol (0 and 50 mM) for 3 days. Both Tbet-expressing (Th1) and FOXP3-expressing (Treg) CD4+ T cells increased after differentiation. Ethanol dysregulated CD4+ T cell differentiation by increasing Th1 and decreasing Treg CD4+ T cell subsets. Ethanol increased glycolysis and impaired oxidative phosphorylation in differentiated CD4+ T cells. Moreover, the glycolytic inhibitor 2-deoxyglucose (2-DG) prevented the ethanol-mediated increase in Tbet-expressing CD4+ T cells but did not attenuate the decrease in FOXP3 expression in differentiated CD4+ T cells. Ethanol increased Treg mitochondrial volume and altered expression of genes implicated in mitophagy and autophagosome formation (PINK1 and ATG7). These results suggest that ethanol impairs CD4+ T cell immunometabolism and disrupts mitochondrial repair processes as it promotes CD4+ T cell differentiation to a pro-inflammatory phenotype.
    Keywords:  CD4+ T cell; alcohol; differentiation; glycolysis; immunometabolism; mitochondria
  5. Cancer Discov. 2022 Jun 02. 12(6): 1405
      Overexpression of PRODH2 augments CAR T-cell proliferation, effector function, and memory phenotype.
  6. Cancer Res. 2022 May 31. pii: canres.4052.2021. [Epub ahead of print]
      Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust anti-tumor immune response. Here, we report that IL-12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumour-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL-12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL-12-stimulated CD8+ T cells and displayed improved anti-tumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T cell therapy.
  7. Front Immunol. 2022 ;13 865492
      Excessive alcohol use increases the risk of developing respiratory infections partially due to impaired alveolar macrophage (AM) phagocytic capacity. Previously, we showed that chronic ethanol (EtOH) exposure led to mitochondrial derangements and diminished oxidative phosphorylation in AM. Since oxidative phosphorylation is needed to meet the energy demands of phagocytosis, EtOH mediated decreases in oxidative phosphorylation likely contribute to impaired AM phagocytosis. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, pioglitazone (PIO), improved EtOH-mediated decreases in oxidative phosphorylation. In other models, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to mediate the switch from oxidative phosphorylation to glycolysis; however, the role of HIF-1α in chronic EtOH mediated derangements in AM has not been explored. We hypothesize that AM undergo a metabolic shift from oxidative phosphorylation to a glycolytic phenotype in response to chronic EtOH exposure. Further, we speculate that HIF-1α is a critical mediator of this metabolic switch. To test these hypotheses, primary mouse AM (mAM) were isolated from a mouse model of chronic EtOH consumption and a mouse AM cell line (MH-S) were exposed to EtOH in vitro. Expression of HIF-1α, glucose transporters (Glut1 and 4), and components of the glycolytic pathway (Pfkfb3 and PKM2), were measured by qRT-PCR and western blot. Lactate levels (lactate assay), cell energy phenotype (extracellular flux analyzer), glycolysis stress tests (extracellular flux analyzer), and phagocytic function (fluorescent microscopy) were conducted. EtOH exposure increased expression of HIF-1α, Glut1, Glut4, Pfkfb3, and PKM2 and shifted AM to a glycolytic phenotype. Pharmacological stabilization of HIF-1α via cobalt chloride treatment in vitro mimicked EtOH-induced AM derangements (increased glycolysis and diminished phagocytic capacity). Further, PIO treatment diminished HIF-1α levels and reversed glycolytic shift following EtOH exposure. These studies support a critical role for HIF-1α in mediating the glycolytic shift in energy metabolism of AM during excessive alcohol use.
    Keywords:  alveolar macrophage; energy metabolism; ethanol; glycolysis; hypoxia-inducible factor-1 alpha
  8. Clin Exp Immunol. 2021 Nov 18. pii: uxab014. [Epub ahead of print]
      Fungal infections affect over a billion people and are responsible for more than 1.5 million deaths each year. Despite progress in diagnostic and therapeutic approaches, the management of severe fungal infections remains a challenge. Recently, the reprogramming of cellular metabolism has emerged as a central mechanism through which the effector functions of immune cells are supported to promote antifungal activity. An improved understanding of the immunometabolic signatures that orchestrate antifungal immunity, together with the dissection of the mechanisms that underlie heterogeneity in individual immune responses, may therefore unveil new targets amenable to adjunctive host-directed therapies. In this review, we highlight recent advances in the metabolic regulation of host-fungus interactions and antifungal immune responses, and outline targetable pathways and mechanisms with promising therapeutic potential.
    Keywords:  antifungal immunity; fungal disease; host-directed therapy; immunometabolism; immunotherapy
  9. Front Immunol. 2022 ;13 882867
      Mitochondria regulate steroid hormone synthesis, and in turn sex hormones regulate mitochondrial function for maintaining cellular homeostasis and controlling inflammation. This crosstalk can explain sex differences observed in several pathologies such as in metabolic or inflammatory disorders. Nod-like receptor X1 (NLRX1) is a mitochondria-associated innate receptor that could modulate metabolic functions and attenuates inflammatory responses. Here, we showed that in an infectious model with the human protozoan parasite, Leishmania guyanensis, NLRX1 attenuated inflammation in females but not in male mice. Analysis of infected female and male bone marrow derived macrophages showed both sex- and genotype-specific differences in both inflammatory and metabolic profiles with increased type I interferon production, mitochondrial respiration, and glycolytic rate in Nlrx1-deficient female BMDMs in comparison to wild-type cells, while no differences were observed between males. Transcriptomics of female and male BMDMs revealed an altered steroid hormone signaling in Nlrx1-deficient cells, and a "masculinization" of Nlrx1-deficient female BMDMs. Thus, our findings suggest that NLRX1 prevents uncontrolled inflammation and metabolism in females and therefore may contribute to the sex differences observed in infectious and inflammatory diseases.
    Keywords:  inflammation; innate immunity; metabolism; nod-like receptor X1; sex
  10. Neurobiol Stress. 2022 Jul;19 100462
      Inflammation is associated with symptoms of anhedonia, a core feature of major depression (MD). We have shown that MD patients with high inflammation as measured by plasma C-reactive protein (CRP) and anhedonia display gene signatures of metabolic reprograming (e.g., shift to glycolysis) necessary to sustain cellular immune activation. To gain preliminary insight into the immune cell subsets and transcriptomic signatures that underlie increased inflammation and its relationship with behavior in MD at the single-cell (sc) level, herein we conducted scRNA-Seq on peripheral blood mononuclear cells from a subset of medically-stable, unmedicated MD outpatients. Three MD patients with high CRP (>3 mg/L) before and two weeks after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab and three patients with low CRP (≤3 mg/L) were studied. Cell clusters were identified using a Single Cell Wizard pipeline, followed by pathway analysis. CD14+ and CD16+ monocytes were more abundant in MD patients with high CRP and were reduced by 29% and 55% respectively after infliximab treatment. Within CD14+ and CD16+ monocytes, genes upregulated in high CRP patients were enriched for inflammatory (phagocytosis, complement, leukocyte migration) and immunometabolic (hypoxia-inducible factor [HIF]-1, aerobic glycolysis) pathways. Shifts in CD4+ T cell subsets included ∼30% and ∼10% lower abundance of CD4+ central memory (TCM) and naïve cells and ∼50% increase in effector memory-like (TEM-like) cells in high versus low CRP patients. TCM cells of high CRP patients displayed downregulation of the oxidative phosphorylation (OXPHOS) pathway, a main energy source in this cell type. Following infliximab, changes in the number of CD14+ monocytes and CD4+ TEM-like cells predicted improvements in anhedonia scores (r = 1.0, p < 0.001). In sum, monocytes and CD4+ T cells from MD patients with increased inflammation exhibited immunometabolic reprograming in association with symptoms of anhedonia. These findings are the first step toward determining the cellular and molecular immune pathways associated with inflammatory phenotypes in MD, which may lead to novel immunomodulatory treatments of psychiatric illnesses with increased inflammation.
    Keywords:  Anhedonia; Depression; Immunometabolism; Inflammation; Monocytes; Single cell RNA-Sequencing; T cells
  11. Cytokine. 2022 May 29. pii: S1043-4666(22)00128-4. [Epub ahead of print]156 155919
      Regulation of macrophage (Mɸ) function can maintain tissue homeostasis and control inflammation. Parasitic worms (helminths) are potent modulators of host immune and inflammatory responses. They have evolved various strategies to promote immunosuppression, including redirecting phagocytic cells toward a regulatory phenotype. Although soluble products from the whipworm Trichuris suis (TSPs) have shown significant effects on Mɸ function, the mechanisms underlying these modulatory effects are still not well understood. In this study, we find that TSPs suppressed inflammatory cytokines (TNF and IL-6) in Mɸs stimulated with a broad panel of TLR agonists, whilst inducing IL-10. Moreover, M1 markers such as MHCII, CD86, iNOS, and TNF were downregulated in TSP-treated Mɸs, without polarizing them towards an M2-like phenotype. We showed that TSPs could establish a suppressed activation state of Mɸs lasting at least for 72 h, indicating an anti-inflammatory innate training. Moreover, we found that TSPs, via repression of intracellular TNF generation, decreased its secretion rather than interfering with the release of surface-bound TNF. Metabolic analysis showed that TSPs promote oxidative phosphorylation (OXPHOS) without affecting glycolytic rate. Collectively, these findings expand our knowledge on helminth-induced immune modulation and support future investigations into the anti-inflammatory properties of TSPs for therapeutic purposes.
    Keywords:  Bone marrow-derived macrophages (BMDMs); Inflammation; Toll-like receptors (TLRs); Trichuris suis soluble products (TSPs)
  12. Front Immunol. 2022 ;13 859116
      GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.
    Keywords:  Mycobacterium tuberculosis; antigen presentation; autophagy; cell death; cellular metabolism; granulocyte macrophage colony-stimulating factor; macrophages; tuberculosis
  13. BMB Rep. 2022 Jun 02. pii: 5619. [Epub ahead of print]
      Recent studies have revealed that the immune system plays a critical role in various physiological processes beyond its classical pathogen control activity. Even under a sterile condition, various cells and tissues can utilize the immune system to meet a specific demand for proper physiological functions. Particularly, a strong link between immunity and metabolism has been identified. Studies have identified the reciprocal regulation between these two systems. For example, immune signals can regulate metabolism, and metabolism (cellular or systemic) can regulate immunity. In this review, we will summarize recent findings on this reciprocal regulation between immunity and metabolism, and discuss potential biological rules behind this interaction with integrative perspectives.
  14. Front Immunol. 2022 ;13 914639
    Keywords:  TCA cycle; immunity; inflammation; itaconate; mitochondria; oxidative stress
  15. J Insect Physiol. 2022 May 28. pii: S0022-1910(22)00047-6. [Epub ahead of print]139 104401
      Invertebrate immune priming has attracted wide attention of biologists in recent years because it challenges core notions about the disparate nature of acquired and innate immunity. However, the metabolic switch and energetic cost during eliciting immune priming are poorly investigated issues, which could widen and deepen our understanding of the physiological mechanism of immune priming. In this study, using sublethal dose of Bacillus thuringiensis (Bt) as an elicitor, we detected typical immune priming responses in Galleria mellonella. We found that the intensity of immune priming is positively correlated with the levels of antimicrobial peptides and phagocytosis ability of hemocytes. Subsequently, we employed LC-MS/MS-based untargeted metabolomics techniques to analyze the metabolic changes in the fat body of G. mellonella larvae during immune priming. The results showed that there were 74 and 56 significantly altered metabolites in positive and negative ion mode, respectively, after Bt priming. Most of the differential metabolites were enriched in the following metabolic pathways: amino acid biosynthesis, carbon metabolism, aminoacyl-tRNA biosynthesis and ABC transporters. The energetic cost of immune priming was depicted mainly in the slow growth of body mass and decreased levels of sucrose, lactose, D-ribulose 1,5-bisphosphate, Glycerate-3P and isocitric acid, which are enriched in carbon metabolism and involved in energy production. Meanwhile, correlation and interaction network analysis showed negative correlations between carbohydrates and metabolites involved in amino acid biosynthesis, suggesting that amino acids acted as the main energy source and helped the organisms synthesize immune effectors to participate in the immune priming response. Our results pave the way for uncovering the physiological mechanism of insect immune priming and discovering novel targets for Bt insecticide.
    Keywords:  Amino acid biosynthesis; Carbon metabolism; Galleria mellonella; Immune priming; Metabolomics
  16. Acta Pharm Sin B. 2022 May;12(5): 2129-2149
      Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.
    Keywords:  AS, atherosclerosis; ASBT, apical sodium-dependent bile salt transporter; BAs, bile acids; BSEP, bile salt export pump; BSH, bile salt hydrolases; Bile acid; CA, cholic acid; CAR, constitutive androstane receptor; CCs, cholesterol crystals; CDCA, chenodeoxycholic acid; CMD, cardiometabolic disease; CVDs, cardiovascular diseases; CYP7A1, cholesterol 7 alpha-hydroxylase; CYP8B1, sterol 12α-hydroxylase; Cardiometabolic diseases; DAMPs, danger-associated molecular patterns; DCA, deoxycholic acid; DCs, dendritic cells; ERK, extracellular signal-regulated kinase; FA, fatty acids; FFAs, free fatty acids; FGF, fibroblast growth factor; FMO3, flavin-containing monooxygenase 3; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide 1; HCA, hyocholic acid; HDL, high-density lipoprotein; HFD, high fat diet; HNF, hepatocyte nuclear receptor; IL, interleukin; IR, insulin resistance; JNK, c-Jun N-terminal protein kinase; LCA, lithocholic acid; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPS, lipopolysaccharide; NAFLD, non-alcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor-κB; NLRP3, NLR family pyrin domain containing 3; Nuclear receptors; OCA, obeticholic acid; PKA, protein kinase A; PPARα, peroxisome proliferator-activated receptor alpha; PXR, pregnane X receptor; RCT, reverses cholesterol transportation; ROR, retinoid-related orphan receptor; S1PR2, sphingosine-1-phosphate receptor 2; SCFAs, short-chain fatty acids; SHP, small heterodimer partner; Systemic immunometabolism; TG, triglyceride; TGR5, takeda G-protein receptor 5; TLR, toll-like receptor; TMAO, trimethylamine N-oxide; Therapeutic opportunities; UDCA, ursodeoxycholic acid; VDR, vitamin D receptor; cAMP, cyclic adenosine monophosphate; mTOR, mammalian target of rapamycin; ox-LDL, oxidated low-density lipoprotein
  17. Mol Omics. 2022 May 31.
      Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS. 4501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during infectious mononucleosis (IM), and at a 6 month follow-up for those who recovered (N = 18) versus those who went on to develop ME/CFS 6 months later (N = 18). Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways. The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response. Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%. These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.
  18. Cell Rep. 2022 May 31. pii: S2211-1247(22)00655-6. [Epub ahead of print]39(9): 110880
      Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable. Here, we show that LL-37, a human host defense peptide, can function as a transporter of cGAMP. LL-37 specifically binds cGAMP and efficiently delivers cGAMP into target cells. cGAMP transferred by LL-37 activates robust interferon responses and host antiviral immunity in a STING-dependent manner. Furthermore, we report that LL-37 inducers vitamin D3 and sodium butyrate promote host immunity by enhancing endogenous LL-37 expression and its mediated cGAMP immune response. Collectively, our data uncover an essential role of LL-37 in innate immune activation and suggest new strategies for immunotherapy.
    Keywords:  CP: Immunology; antibacterial peptide; cGAMP; cGAS-STING signaling pathway; innate immunity; type I interferon
  19. Immunometabolism. 2022 ;pii: e220013. [Epub ahead of print]4(2):
      People living with HIV (PLWH) who are immune non-responders (INR) to therapy are unable to restore their CD4 T-cell count and remain at great risk of morbidity and mortality. Here the mitochondrial defects that characterize memory CD4 T-cells in INR and causes of this mitochondrial exhaustion are reviewed. This review also describes the various reagents used to induce the expression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis, which can restore mitochondria fitness and CD4 T-cell proliferation in INR. Due to sustained heightened inflammation in INR, the mitochondrial network is unable to be rejuvenated and requires attenuation of mediators of inflammation to rescue mitochondria and CD4 T-cell counts in INR.
    Keywords:  CD4 T-cells; exhaustion; mitochondria; pgc1α
  20. J Mol Med (Berl). 2022 Jun;100(6): 963-971
      Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A > G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74-79% lower responses for IL-6 and IL-1β (pIL-6 = 0.031, pIL-1β = 0.009). Moreover, whole blood from patients with mtDNA deletions (pIL-6 = 0.006), but not patients with the m.3243A > G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocorticoids. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes. KEY MESSAGES: Little is known about leukocyte cytokine responses in patients with mitochondrial diseases. Leukocytes of patients with mtDNA deletions show blunted LPS sensitivity and cytokine responses. Leukocytes of patients with mtDNA deletions are more sensitive to glucocorticoid-mediated IL-6 suppression. Work in larger cohorts is needed to delineate potential immune alterations in mitochondrial diseases.
    Keywords:  3243A > G; Cytokine; Glucocorticoid; Inflammation; Inflammation Suppression; Interleukin; Mitochondrial disease; mtDNA deletion
  21. EMBO J. 2022 May 31. e110636
      Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8+ T cells. Here, we found that disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte-specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin-2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti-tumor immunity against both melanoma and colon cancer in mice by activating CD8+ T cells, and this effect was enhanced by anti-PD-1 co-treatment. We conclude that DSF directly activates LCK-mediated TCR signaling to induce strong anti-tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer.
    Keywords:  LCK; T cell receptor; cancer immunotherapy; disulfiram; drug repurposing
  22. Antibodies (Basel). 2022 Apr 30. pii: 32. [Epub ahead of print]11(2):
      Adoptive cell therapy holds great promise for treating a myriad of diseases, especially cancer. Within the last decade, immunotherapy has provided a significant leap in the successful treatment of leukemia. The research conducted throughout this period to understand the interrelationships between cancer cells and infiltrating immune cells winds up having one very common feature, bioenergetics. Cancer cells and immune cells both need ATP to perform their individual functions and cancer cells have adopted means to limit immune cell activity via changes in immune cell bioenergetics that redirect immune cell behavior to encourage tumor growth. Current leading strategies for cancer treatment super-charge an individual's own immune cells against cancer. Successful Chimeric Antigen Receptor T Cells (CAR T) target pathways that ultimately influence bioenergetics. In the last decade, scientists identified that mitochondria play a crucial role in T cell physiology. When modifying T cells to create chimeras, a unique mitochondrial fitness emerges that establishes stemness and persistence. This review highlights many of the key findings leading to this generation's CAR T treatments and the work currently being done to advance immunotherapy, to empower not just T cells but other immune cells as well against a variety of cancers.
    Keywords:  CAR T; bioenergetics; immunotherapy; metabolism
  23. Front Cell Dev Biol. 2022 ;10 808859
      Tumor evolution is influenced by events involving tumor cells and the environment in which they live, known as the tumor microenvironment (TME). TME is a functional and structural niche composed of tumor cells, endothelial cells (ECs), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), and a subset of immune cells (macrophages, dendritic cells, natural killer cells, T cells, B cells). Otto Warburg revealed the Warburg effect in 1923, a characteristic metabolic mechanism of tumor cells that performs high glucose uptake and excessive lactate formation even in abundant oxygen. Tumor tissues excrete a large amount of lactate into the extracellular microenvironment in response to TME's hypoxic or semi-hypoxic state. High lactate concentrations in tumor biopsies have been linked to metastasis and poor clinical outcome. This indicates that the metabolite may play a role in carcinogenesis and lead to immune escape in TME. Lactate is now recognized as an essential carbon source for cellular metabolism and as a signaling molecule in TME, forming an active niche that influences tumor progression. This review summarized the advanced literature demonstrating the functional role of lactate in TME remodeling, elucidating how lactate shapes the behavior and the phenotype of both tumor cells and tumor-associated cells. We also concluded the intriguing interactions of multiple immune cells in TME. Additionally, we demonstrated how lactate functioned as a novel function factor by being used in a new histone modification, histone lysine lactylation, and to regulate gene expression in TME. Ultimately, because lactate created a favorable niche for tumor progression, we summarized potential anti-tumor strategies targeting lactate metabolism and signaling to investigate better cancer treatment.
    Keywords:  energy source; immune response; lactate; lactylation; tumor micoenvironment
  24. Nat Commun. 2022 Jun 02. 13(1): 3072
      Recognition of pathogen-or-damage-associated molecular patterns is critical to inflammation. However, most pathogen-or-damage-associated molecular patterns exist within intact microbes/cells and are typically part of non-diffusible, stable macromolecules that are not optimally immunostimulatory or available for immune detection. Partial digestion of microbes/cells following phagocytosis potentially generates new diffusible pathogen-or-damage-associated molecular patterns, however, our current understanding of phagosomal biology would have these molecules sequestered and destroyed within phagolysosomes. Here, we show the controlled release of partially-digested, soluble material from phagolysosomes of macrophages through transient, iterative fusion-fission events between mature phagolysosomes and the plasma membrane, a process we term eructophagy. Eructophagy is most active in proinflammatory macrophages and further induced by toll like receptor engagement. Eructophagy is mediated by genes encoding proteins required for autophagy and can activate vicinal cells by release of phagolysosomally-processed, partially-digested pathogen associated molecular patterns. We propose that eructophagy allows macrophages to amplify local inflammation through the processing and dissemination of pathogen-or-damage-associated molecular patterns.