ABSTRACT
Chronic infection with Schistosoma mansoni parasites is associated with reduced allergic sensitization in humans, while schistosome eggs protects against allergic airway inflammation (AAI) in mice. One of the main secretory/excretory molecules from schistosome eggs is the glycosylated T2-RNAse Omega-1 (ω1). We hypothesized that ω1 induces protection against AAI during infection. Peritoneal administration of ω1 prior to sensitization with Ovalbumin (OVA) reduced airway eosinophilia and pathology, and OVA-specific Th2 responses upon challenge, independent from changes in regulatory T cells. ω1 was taken up by monocyte-derived dendritic cells, mannose receptor (CD206)-positive conventional type 2 dendritic cells (CD206+ cDC2), and by recruited peritoneal macrophages. Additionally, ω1 impaired CCR7, F-actin, and costimulatory molecule expression on myeloid cells and cDC2 migration in and ex vivo, as evidenced by reduced OVA+ CD206+ cDC2 in the draining mediastinal lymph nodes (medLn) and retainment in the peritoneal cavity, while antigen processing and presentation in cDC2 were not affected by ω1 treatment. Importantly, RNAse mutant ω1 was unable to reduce AAI or affect DC migration, indicating that ω1 effects are dependent on its RNAse activity. Altogether, ω1 hampers migration of OVA+ cDC2 to the draining medLn in mice, elucidating how ω1 prevents allergic airway inflammation in the OVA/alum mouse model.
ABSTRACT
Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.
Subject(s)
CD36 Antigens/immunology , Fatty Acids/metabolism , Interleukin-4/immunology , Lipolysis/immunology , Lysosomes/immunology , Macrophage Activation/immunology , Macrophages/immunology , Oxidative Phosphorylation , Signal Transduction/immunology , Sterol Esterase/immunology , Animals , Cell Respiration , Helminthiasis, Animal/immunology , Humans , Mice , Oxygen Consumption , Receptors, Interleukin-4/immunology , TranscriptomeABSTRACT
The ligation of Toll-like receptors (TLRs) leads to rapid activation of dendritic cells (DCs). However, the metabolic requirements that support this process remain poorly defined. We found that DC glycolytic flux increased within minutes of exposure to TLR agonists and that this served an essential role in supporting the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi required for the production and secretion of proteins that are integral to DC activation. Signaling via the kinases TBK1, IKKÉ and Akt was essential for the TLR-induced increase in glycolysis by promoting the association of the glycolytic enzyme HK-II with mitochondria. In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs.
Subject(s)
Dendritic Cells/immunology , Glycolysis , I-kappa B Kinase/metabolism , Protein Serine-Threonine Kinases/metabolism , T-Lymphocytes/immunology , Animals , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cells, Cultured , Fatty Acids/biosynthesis , Glycolysis/drug effects , Glycolysis/genetics , Glycolysis/immunology , Hexokinase/metabolism , I-kappa B Kinase/genetics , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Toll-Like Receptors/agonistsABSTRACT
Cellular metabolism is a key determinant of immune cell function. Here we found that CD14+ monocytes from Sub-Saharan Africans produce higher levels of IL-10 following TLR-4 stimulation and are bioenergetically distinct from monocytes from Europeans. Through metabolomic profiling, we identified the higher IL-10 production to be driven by increased baseline production of NADPH oxidase-dependent reactive oxygen species, supported by enhanced pentose phosphate pathway activity. Together, these data indicate that NADPH oxidase-derived ROS is a metabolic checkpoint in monocytes that governs their inflammatory profile and uncovers a metabolic basis for immunological differences across geographically distinct populations.
ABSTRACT
Macrophage activation status is intrinsically linked to metabolic remodeling. Macrophages stimulated by interleukin 4 (IL-4) to become alternatively (or, M2) activated increase fatty acid oxidation and oxidative phosphorylation; these metabolic changes are critical for M2 activation. Enhanced glucose utilization is also characteristic of the M2 metabolic signature. Here, we found that increased glucose utilization is essential for M2 activation. Increased glucose metabolism in IL-4-stimulated macrophages required the activation of the mTORC2 pathway, and loss of mTORC2 in macrophages suppressed tumor growth and decreased immunity to a parasitic nematode. Macrophage colony stimulating factor (M-CSF) was implicated as a contributing upstream activator of mTORC2 in a pathway that involved PI3K and AKT. mTORC2 operated in parallel with the IL-4Rα-Stat6 pathway to facilitate increased glycolysis during M2 activation via the induction of the transcription factor IRF4. IRF4 expression required both mTORC2 and Stat6 pathways, providing an underlying mechanism to explain how glucose utilization is increased to support M2 activation.
Subject(s)
Interferon Regulatory Factors/metabolism , Macrophage Activation/physiology , Macrophages/physiology , Multiprotein Complexes/metabolism , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Animals , Interleukin-4/metabolism , Macrophage Colony-Stimulating Factor/metabolism , Macrophages/metabolism , Mechanistic Target of Rapamycin Complex 2 , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , STAT6 Transcription Factor/metabolismABSTRACT
Greater understanding of the complex host responses induced by type 1 interferon (IFN) cytokines could allow new therapeutic approaches for diseases in which these cytokines are implicated. We found that in response to the Toll-like receptor-9 agonist CpGA, plasmacytoid dendritic cells (pDC) produced type 1 IFNs, which, through an autocrine type 1 IFN receptor-dependent pathway, induced changes in cellular metabolism characterized by increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Direct inhibition of FAO and of pathways that support this process, such as fatty acid synthesis, prevented full pDC activation. Type 1 IFNs also induced increased FAO and OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO and OXPHOS in virus-infected cells. Increased FAO and OXPHOS in response to type 1 IFNs was regulated by PPARα. Our findings reveal FAO, OXPHOS and PPARα as potential targets to therapeutically modulate downstream effects of type 1 IFNs.
Subject(s)
Dendritic Cells/immunology , Interferon Type I/metabolism , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/immunology , PPAR alpha/metabolism , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Acetyl-CoA C-Acyltransferase/metabolism , Animals , Carbon-Carbon Double Bond Isomerases/metabolism , Cell Differentiation , Cells, Cultured , CpG Islands/immunology , Enoyl-CoA Hydratase/metabolism , Gene Expression Regulation , Immunity , Lipid Metabolism , Mice , Mice, Inbred C57BL , Oligodeoxyribonucleotides/immunology , Oxidative Phosphorylation , Racemases and Epimerases/metabolism , Receptors, Interferon/metabolism , Signal Transduction , Toll-Like Receptor 9/metabolismABSTRACT
Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.
Subject(s)
Gene Regulatory Networks/immunology , Immunity, Innate , Macrophages/metabolism , Mitochondria/metabolism , Transcription, Genetic/immunology , Animals , Argininosuccinic Acid/immunology , Argininosuccinic Acid/metabolism , Aspartate Aminotransferase, Mitochondrial/genetics , Aspartate Aminotransferase, Mitochondrial/immunology , Aspartic Acid/immunology , Aspartic Acid/metabolism , Chemokine CCL22/genetics , Chemokine CCL22/immunology , Citric Acid Cycle , Gene Expression Regulation , Glutamine/deficiency , Glycosylation , Interleukin-6/genetics , Interleukin-6/immunology , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/immunology , Macrophages/classification , Macrophages/cytology , Macrophages/immunology , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Mice , Mitochondria/genetics , Mitochondria/immunology , Nitric Oxide/immunology , Nitric Oxide/metabolism , Signal Transduction , Uridine Diphosphate N-Acetylglucosamine/immunology , Uridine Diphosphate N-Acetylglucosamine/metabolismABSTRACT
The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2, but not Th17, cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite (HDM) challenge without affecting cytotoxic T lymphocyte (CTL), Th1 cell, or Th17 cell responses to herpes simplex virus, Toxoplasma gondii, and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity.
Subject(s)
Dendritic Cells/immunology , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Schistosomiasis mansoni/immunology , Th2 Cells/immunology , Animals , Antigens, Helminth/immunology , Asthma/immunology , Cells, Cultured , Dendritic Cells/metabolism , Disease Models, Animal , Enterobacteriaceae Infections/immunology , Gene Deletion , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Herpes Simplex/immunology , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/immunology , Kruppel-Like Factor 4 , Mice , Mice, Inbred C57BL , Pyroglyphidae , Th2 Cells/cytology , Toxoplasmosis/immunologyABSTRACT
Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB-mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.
Subject(s)
Gene Expression Regulation/drug effects , Macrophage Activation/drug effects , Macrophages/metabolism , Mannose Receptor/chemistry , Membrane Proteins/pharmacology , Animal Feed , Animals , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Diet, High-Fat , Gastrointestinal Microbiome , Inflammation , Macrophage Activation/physiology , Male , Mannose Receptor/metabolism , Mice , Mice, Knockout , Random AllocationABSTRACT
In recent years there have been major advances in our understanding of the role of free fatty acids (FAs) and their metabolism in shaping the functional properties of macrophages and DCs. This review presents the most recent insights into how cell intrinsic FA metabolism controls DC and macrophage function, as well as the current evidence of the importance of various exogenous FAs (such as polyunsaturated FAs and their oxidation products-prostaglandins, leukotrienes, and proresolving lipid mediators) in affecting DC and macrophage biology, by modulating their metabolic properties. Finally, we explore whether targeted modulation of FA metabolism of myeloid cells to steer their function could hold promise in therapeutic settings.
Subject(s)
Dendritic Cells/immunology , Fatty Acids/immunology , Macrophages/immunology , Animals , Humans , Lipid Metabolism/immunology , Myeloid Cells/immunologyABSTRACT
Professional antigen-presenting cells (APCs), like macrophages (MÏs) and dendritic cells (DCs), are central players in the induction of natural and vaccine-induced immunity to malaria, yet very little is known about the interaction of SPZ with human APCs. Intradermal delivery of whole-sporozoite vaccines reduces their effectivity, possibly due to dermal immunoregulatory effects. Therefore, understanding these interactions could prove pivotal to malaria vaccination. We investigated human APC responses to recombinant circumsporozoite protein (recCSP), SPZ and anti-CSP opsonized SPZ both in monocyte derived MoDCs and MoMÏs. Both MoDCs and MoMÏs readily took up recCSP but did not change phenotype or function upon doing so. SPZ are preferentially phagocytosed by MoMÏs instead of DCs and phagocytosis greatly increased after opsonization. Subsequently MoMÏs show increased surface marker expression of activation markers as well as tolerogenic markers such as Programmed Death-Ligand 1 (PD-L1). Additionally they show reduced motility, produce interleukin 10 and suppressed interferon gamma (IFNγ) production by antigen specific CD8+ T cells. Importantly, we investigated phenotypic responses to SPZ in primary dermal APCs isolated from human skin explants, which respond similarly to their monocyte-derived counterparts. These findings are a first step in enhancing our understanding of pre-erythrocytic natural immunity and the pitfalls of intradermal vaccination-induced immunity.
Subject(s)
Antigen-Presenting Cells/immunology , Macrophages/immunology , Malaria/immunology , Plasmodium berghei/immunology , Protozoan Proteins/immunology , Skin/immunology , Sporozoites/immunology , Animals , Cells, Cultured , Female , Humans , Macrophages/parasitology , Malaria/parasitology , Mice , Skin/parasitologyABSTRACT
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.
Subject(s)
Trichuriasis , Trichuris , Animals , Anti-Inflammatory Agents/pharmacology , Cells, Cultured , Cytokines/metabolism , Macrophages/metabolism , Trichuriasis/metabolism , Trichuriasis/parasitology , Trichuris/metabolismABSTRACT
IgG Abs are crucial for various immune functions, including neutralization, phagocytosis, and Ab-dependent cellular cytotoxicity. In this study, we identified another function of IgG by showing that IgG immune complexes elicit distinct cytokine profiles by human myeloid immune cells, which are dependent on FcγR activation by the different IgG subclasses. Using monoclonal IgG subclasses with identical Ag specificity, our data demonstrate that the production of Th17-inducing cytokines, such as TNF, IL-1ß, and IL-23, is particularly dependent on IgG2, whereas type I IFN responses are controlled by IgG3, and IgG1 is able to regulate both. In addition, we identified that subclass-specific cytokine production is orchestrated at the posttranscriptional level through distinct glycolytic reprogramming of human myeloid immune cells. Combined, these data identify that IgG subclasses provide pathogen- and cell type-specific immunity through differential metabolic reprogramming by FcγRs. These findings may be relevant for future design of Ab-related therapies in the context of infectious diseases, chronic inflammation, and cancer.
Subject(s)
Cytokines/immunology , Immunoglobulin G/immunology , Myeloid Cells/immunology , Receptors, IgG/immunology , Humans , Myeloid Cells/cytologyABSTRACT
CD8(+) T cells undergo major metabolic changes upon activation, but how metabolism influences the establishment of long-lived memory T cells after infection remains a key question. We have shown here that CD8(+) memory T cells, but not CD8(+) T effector (Teff) cells, possessed substantial mitochondrial spare respiratory capacity (SRC). SRC is the extra capacity available in cells to produce energy in response to increased stress or work and as such is associated with cellular survival. We found that interleukin-15 (IL-15), a cytokine critical for CD8(+) memory T cells, regulated SRC and oxidative metabolism by promoting mitochondrial biogenesis and expression of carnitine palmitoyl transferase (CPT1a), a metabolic enzyme that controls the rate-limiting step to mitochondrial fatty acid oxidation (FAO). These results show how cytokines control the bioenergetic stability of memory T cells after infection by regulating mitochondrial metabolism.
Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Mitochondria/metabolism , Animals , CD8-Positive T-Lymphocytes/enzymology , Carnitine O-Palmitoyltransferase/metabolism , Cell Respiration/physiology , Fatty Acids/metabolism , Flow Cytometry , Interleukin-15/metabolism , Mice , Mice, Inbred C57BL , Mitochondria/enzymology , Models, Biological , Oxidation-Reduction , Real-Time Polymerase Chain ReactionABSTRACT
The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1-independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2-/-, and to a lesser extent Dectin-1-/- mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced.
Subject(s)
Dendritic Cells/immunology , Dinoprostone/immunology , Lectins, C-Type/immunology , Schistosoma mansoni/immunology , Schistosomiasis mansoni/immunology , Th2 Cells/immunology , Animals , Antigens, Helminth/immunology , Antigens, Helminth/pharmacology , Autocrine Communication , Cell Differentiation , Cyclooxygenase 1/genetics , Cyclooxygenase 1/immunology , Cyclooxygenase 2/genetics , Cyclooxygenase 2/immunology , Dendritic Cells/drug effects , Dendritic Cells/parasitology , Dinoprostone/metabolism , Enterotoxins/pharmacology , Gene Expression Regulation , Humans , Lectins, C-Type/deficiency , Lectins, C-Type/genetics , MAP Kinase Signaling System , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , OX40 Ligand , Phospholipases A2/genetics , Phospholipases A2/immunology , Primary Cell Culture , Reactive Oxygen Species/immunology , Reactive Oxygen Species/metabolism , Schistosomiasis mansoni/genetics , Schistosomiasis mansoni/parasitology , Schistosomiasis mansoni/pathology , Syk Kinase/genetics , Syk Kinase/immunology , Th2 Cells/drug effects , Th2 Cells/parasitology , Tumor Necrosis Factors/genetics , Tumor Necrosis Factors/immunologyABSTRACT
C-reactive protein (CRP) is an acute-phase protein produced in high quantities by the liver in response to infection and during chronic inflammatory disorders. Although CRP is known to facilitate the clearance of cell debris and bacteria by phagocytic cells, the role of CRP in additional immunological functions is less clear. This study shows that complexed CRP (phosphocholine [PC]:CRP) (formed by binding of CRP to PC moieties), but not soluble CRP, synergized with specific TLRs to posttranscriptionally amplify TNF, IL-1ß, and IL-23 production by human inflammatory macrophages. We identified FcγRI and IIa as the main receptors responsible for initiating PC:CRP-induced inflammation. In addition, we identified the underlying mechanism, which depended on signaling through kinases Syk, PI3K, and AKT2, as well as glycolytic reprogramming. These data indicate that in humans, CRP is not only a marker but also a driver of inflammation by human macrophages. Therefore, although providing host defense against bacteria, PC:CRP-induced inflammation may also exacerbate pathology in the context of disorders such as atherosclerosis.
Subject(s)
C-Reactive Protein/metabolism , Inflammation/immunology , Liver/physiology , Receptors, IgG/metabolism , Atherosclerosis/immunology , C-Reactive Protein/chemistry , Cells, Cultured , Cellular Reprogramming , Cytokines/metabolism , Glycolysis , Humans , Inflammation Mediators/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylcholine/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Syk Kinase/metabolism , Toll-Like Receptors/metabolismABSTRACT
Mounting an effective immune response is crucial for the host to protect itself against invading pathogens. It is now well appreciated that reprogramming of core metabolic pathways in immune cells is a key requirement for their activation and function during infections. The role of several ancillary metabolic pathways in shaping immune cell function is less well understood. One such pathway, for which interest has recently been growing, is the hexosamine biosynthesis pathway (HBP) that generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the donor substrate for a specific form of glycosylation termed O-GlcNAcylation. O-GlcNAc is an intracellular post-translational modification that alters the functional properties of the modified proteins, in particular transcription factors and epigenetic regulators. An increasing number of studies suggest a central role for the HBP and O-GlcNAcylation in dictating immune cell function, including the response to different pathogens. We here discuss the most recent insights regarding O-GlcNAcylation and immunity, and explore whether targeting of O-GlcNAcylation could hold promise as a therapeutic approach to modulate immune responses to infections.
Subject(s)
Glucosamine/analogs & derivatives , Infections/immunology , beta-N-Acetylhexosaminidases/metabolism , Animals , Epigenesis, Genetic , Glucosamine/metabolism , Glycosylation , Hexosamines/biosynthesis , Humans , Immunity , ImmunomodulationABSTRACT
Type 2 immune responses play key roles in protection against parasitic worm infections, whole-body metabolic homeostasis, wound healing, and the development of allergies. As a result, there is considerable interest in understanding the pathways that regulate type 2 immunity in order to identify strategies of targeting and controlling these responses. In recent years, it has become increasingly clear that the functional properties of immune cells, including those involved in type 2 immune responses, are dependent on the engagement of specific metabolic pathways such as aerobic glycolysis and fatty acid oxidation (FAO). We here discuss the latest insights in the metabolic regulation of immune cells that initiate type 2 immune responses, such as dendritic cells and innate lymphoid cells, as well as immune cells involved in the effector phase, like T helper 2 (Th2) cells, B cells and alternatively activated macrophages (M2 macrophages). Finally, we consider whether these findings may provide new prospects for the treatment of type 2 immune response-associated diseases.
Subject(s)
Dendritic Cells/immunology , Immunity, Innate , Th2 Cells/immunology , Animals , Dendritic Cells/metabolism , Gene Expression Regulation , Glycolysis , Humans , Lymphocytes/immunology , Macrophage Activation , Macrophages/immunology , Mice , Oxidative Phosphorylation , Signal Transduction , Th2 Cells/metabolismABSTRACT
BACKGROUND: Dendritic cells (DCs) are the sentinels of the immune system. Upon recognition of a pathogen, they mature and migrate to draining lymph nodes to prime and polarize T cell responses. Although it is known that helminths and helminth-derived molecules condition DCs to polarize T helper (Th) cells towards Th2, the underlying mechanisms remain incompletely understood. OBJECTIVES: The aim of this study was to conduct a proteome analysis of helminth antigen-stimulated DCs in order to gain more insight into the cellular processes associated with their ability to polarize immune responses. METHODS: We analyzed the maturation and polarization of monocyte-derived DCs from 9 donors at 2 different time points after stimulation with different Th1- and Th2-polarizing pathogen-derived molecules. The samples were measured using liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry for relative quantitation. RESULTS: Lipopolysaccharide-induced maturation promoted the expression of proteins related to metabolic, cellular, and immune system processes. Th1-polarizing DCs, conditioned by IFN-γ during maturation, displayed accelerated maturation by differentially expressing cytoskeletal proteins and proteins involved in immune regulation. The stimulation of DCs with soluble egg antigens and omega-1 derived from Schistosoma mansoni, which are both Th2-inducing stimuli, increased 60S acidic ribosomal protein P2, and vesicle amine transferase 1 while decreasing the expression of proteins related to antigen processing and presentation. CONCLUSION: Our data indicate that not only proteins involved in the interaction between T cells and DCs at the level of the immunological synapse, but also those related to cellular metabolism and stress, may promote Th2 polarization.
Subject(s)
Dendritic Cells/immunology , Schistosoma mansoni/immunology , Schistosomiasis mansoni/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Animals , Antigen Presentation , Antigens, Helminth/immunology , Cell Differentiation , Cells, Cultured , Egg Proteins/immunology , Humans , Immune Evasion , Interferon-gamma/immunology , Lipopolysaccharides/immunology , ProteomicsABSTRACT
Humoral immunity requires cross-talk between T follicular helper (Tfh) cells and B cells. Nevertheless, a detailed understanding of this intercellular interaction during secondary immune responses is lacking. We examined this by focusing on the response to a soluble, unadjuvanted, pathogen-derived Ag (soluble extract of Schistosoma mansoni egg [SEA]) that induces type 2 immunity. We found that activated Tfh cells persisted for long periods within germinal centers following primary immunization. However, the magnitude of the secondary response did not appear to depend on pre-existing Tfh cells. Instead, Tfh cell populations expanded through a process that was dependent on memory T cells recruited into the reactive LN, as well as the participation of B cells. We found that, during the secondary response, IL-4 was critical for the expansion of a population of plasmablasts that correlated with increased SEA-specific IgG1 titers. Additionally, following immunization with SEA (but not with an Ag that induced type 1 immunity), IL-4 and IL-21 were coproduced by individual Tfh cells, revealing a potential mechanism through which appropriate class-switching can be coupled to plasmablast proliferation to enforce type 2 immunity. Our findings demonstrate a pivotal role for IL-4 in the interplay between T and B cells during a secondary Th2 response and have significant implications for vaccine design.