ABSTRACT
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle-derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
Subject(s)
Citric Acid Cycle , Immunity , Macrophages/immunology , Macrophages/metabolism , Animals , Disease Susceptibility , Energy Metabolism , Humans , Immunomodulation , Macrophage Activation/immunology , Signal TransductionABSTRACT
Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is termed adaptive immunity, which involves the exquisitely specific activities of lymphocytes. But the other arm of immunity, so-called "innate immunity," had been neglected. To celebrate Cell's 50th anniversary, we have put together a review of the processes and components of innate immunity and trace the seminal contributions leading to the modern state of this field. Innate immunity has joined adaptive immunity in the center of interest for all those who study the body's defenses, as well as homeostasis and pathology. We are now entering the era where therapeutic targeting of innate immune receptors and downstream signals hold substantial promise for infectious and inflammatory diseases and cancer.
Subject(s)
Immunity, Innate , Humans , Animals , History, 20th Century , History, 21st Century , Adaptive Immunity , Allergy and Immunology/historyABSTRACT
Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.
Subject(s)
Killer Cells, Natural , Single-Cell Analysis , Humans , Single-Cell Analysis/methods , Killer Cells, Natural/immunology , Transcriptome , Neoplasms/immunology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Palatine Tonsil/immunology , Palatine Tonsil/cytology , Gene Expression Profiling , Lung/immunology , Cytokines/metabolismABSTRACT
Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.
Subject(s)
Citric Acid Cycle/physiology , Succinates/metabolism , Succinic Acid/metabolism , Animals , Humans , Signal TransductionABSTRACT
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
Subject(s)
Inflammation/immunology , Macrophage Activation , Macrophages/immunology , Mitochondria/enzymology , Succinate Dehydrogenase/metabolism , Succinic Acid/metabolism , Adenosine Triphosphate/metabolism , Animals , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Citric Acid Cycle , Glycolysis , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inflammation/genetics , Interleukin-10/metabolism , Lipopolysaccharides/immunology , Macrophages/metabolism , Malonates/pharmacology , Membrane Potential, Mitochondrial , Mice , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondrial Proteins/metabolism , Oxidation-Reduction/drug effects , Oxidative Phosphorylation/drug effects , Oxidoreductases/metabolism , Plant Proteins/metabolism , Reactive Oxygen Species/metabolism , Sequence Analysis, RNA , Succinate Dehydrogenase/genetics , TranscriptomeABSTRACT
Much more than the "powerhouse" of the cell, mitochondria have emerged as critical hubs involved in metabolism, cell death, inflammation, signaling, and stress responses. To open our mitochondria focus issue, we asked several scientists to share the unanswered questions, emerging themes, and topics of investigation that excite them.
Subject(s)
Mitochondria , Signal Transduction , Humans , Mitochondria/metabolism , Cell Death , Inflammation/metabolismABSTRACT
York et al. identify a role for decreased cholesterol biosynthesis in virally infected cells as a critical event in the induction of the anti-viral response. The mechanism involves enhanced signaling by STING in the ER membrane in response to the second messenger cGAMP, promoting increased transcription of type I interferons. The authors suggest that a "lipid code" is being sensed by STING to allow it to signal.
Subject(s)
Cholesterol/metabolism , Immunity, Innate , Interferon-gamma/metabolism , Signal Transduction , Animals , HumansABSTRACT
Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.
Subject(s)
Inflammation , Mitochondria , Models, Biological , Symbiosis , Humans , Autoimmune Diseases/etiology , Autoimmune Diseases/metabolism , Autoimmune Diseases/pathology , Diet/adverse effects , Homeostasis , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/physiology , Mitochondrial Proteins/metabolism , Nucleic Acids/metabolism , Obesity/complications , Obesity/metabolism , Obesity/pathology , Phospholipids/metabolism , Reactive Oxygen Species/metabolism , Symbiosis/physiology , AnimalsABSTRACT
Recent evidence indicates that mitochondria lie at the heart of immunity. Mitochondrial DNA acts as a danger-associated molecular pattern (DAMP), and the mitochondrial outer membrane is a platform for signaling molecules such as MAVS in RIG-I signaling, and for the NLRP3 inflammasome. Mitochondrial biogenesis, fusion and fission have roles in aspects of immune-cell activation. Most important, Krebs cycle intermediates such as succinate, fumarate and citrate engage in processes related to immunity and inflammation, in both innate and adaptive immune cells. These discoveries are revealing mitochondrial targets that could potentially be exploited for therapeutic gain in inflammation and cancer.
Subject(s)
Adaptive Immunity , Citric Acid Cycle/immunology , Immunity, Innate , Mitochondria/immunology , Mitochondrial Membranes/immunology , Animals , DEAD Box Protein 58/metabolism , Energy Metabolism , Humans , Immunomodulation , Inflammasomes/metabolism , Lymphocyte Activation , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Receptors, Immunologic , Receptors, Pattern Recognition/metabolism , Signal TransductionABSTRACT
Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.
Subject(s)
Communicable Diseases/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Inflammation/immunology , Acute Disease , Chronic Disease , HumansABSTRACT
Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-ß production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.
Subject(s)
Fumarate Hydratase , Interferon-beta , Macrophages , Mitochondria , RNA, Mitochondrial , Humans , Argininosuccinate Synthase/metabolism , Argininosuccinic Acid/metabolism , Aspartic Acid/metabolism , Cell Respiration , Cytosol/metabolism , Fumarate Hydratase/antagonists & inhibitors , Fumarate Hydratase/genetics , Fumarate Hydratase/metabolism , Fumarates/metabolism , Interferon-beta/biosynthesis , Interferon-beta/immunology , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Lupus Erythematosus, Systemic/enzymology , Macrophages/enzymology , Macrophages/immunology , Macrophages/metabolism , Membrane Potential, Mitochondrial , Metabolomics , Mitochondria/genetics , Mitochondria/metabolism , RNA, Mitochondrial/metabolismSubject(s)
Allergy and Immunology , Biomedical Research , Immune System/immunology , Inflammation Mediators/immunology , Inflammation/immunology , Animals , Anti-Inflammatory Agents/therapeutic use , Diffusion of Innovation , Drug Discovery , Humans , Immune System/drug effects , Immune System/metabolism , Immune System/pathology , Immunotherapy , Inflammation/diagnosis , Inflammation/drug therapy , Inflammation/metabolism , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Molecular Targeted Therapy , Signal TransductionABSTRACT
Metabolites have functions in the immune system independent of their conventional roles as sources or intermediates in biosynthesis and bioenergetics. We are still in the pioneering phase of gathering information about the functions of specific metabolites in immunoregulation. In this review, we cover succinate, itaconate, α-ketoglutarate, and lactate as examples. Each of these metabolites has a different story of how their immunoregulatory functions were discovered and how their roles in the complex process of inflammation were revealed. Parallels and interactions are emerging between metabolites and cytokines, well-known immunoregulators. We depict molecular mechanisms by which metabolites prime cellular and often physiological changes focusing on intra- and extra-cellular activities and signaling pathways. Possible therapeutic opportunities for immune and inflammatory diseases are emerging.
Subject(s)
Carboxylic Acids/immunology , Carboxylic Acids/metabolism , Immunity/immunology , Animals , Citric Acid Cycle , Cytokines/metabolism , Energy Metabolism , Humans , Immunity/physiology , Inflammation/metabolism , Ketoglutaric Acids/immunology , Ketoglutaric Acids/metabolism , Lactic Acid/immunology , Lactic Acid/metabolism , Signal Transduction , Succinates/immunology , Succinates/metabolism , Succinic Acid/immunology , Succinic Acid/metabolismABSTRACT
Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.