Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate’s emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.
Christian G. Peace, Luke A.J. O’Neill
Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.
Mauro Corrado, Erika L. Pearce
Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.
Kathryn M. Lemberg, Sadakatali S. Gori, Takashi Tsukamoto, Rana Rais, Barbara S. Slusher
The rapid invention of genome-editing technologies over the past decade, which has already been transformative for biomedical research, has raised the tantalizing prospect of an entirely new therapeutic modality. Whereas the treatment of chronic cardiovascular diseases has heretofore entailed the use of chronic therapies that typically must be taken repeatedly and frequently for the remainder of the lifetime, genome editing will enable the development of “one-and-done” therapies with durable effects. This Review summarizes the variety of available genome-editing approaches, including nuclease editing, base editing, epigenome editing, and prime editing; illustrates how these various approaches could be implemented as novel therapies for cardiovascular diseases; and outlines a path from technology development to preclinical studies to clinical trials. Although this Review focuses on PCSK9 as an instructive example of the various genome-editing approaches under active investigation, the lessons learned will be broadly applicable to the treatment of a variety of diseases.
Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.
Alan R. Tall, David G. Thomas, Ainara G. Gonzalez-Cabodevilla, Ira J. Goldberg
Acute coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Disease Association (AARDA) Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10 to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.
Jason S. Knight, Roberto Caricchio, Jean Laurent Casanova, Alexis J. Combes, Betty Diamond, Sharon E. Fox, David A. Hanauer, Judith A. James, Yogendra Kanthi, Virginia Ladd, Puja Mehta, Aaron M. Ring, Ignacio Sanz, Carlo Selmi, Russell P. Tracy, Paul J. Utz, Catriona A. Wagner, Julia Y. Wang, W. Joseph McCune
Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the preconceived notion that fibroblasts are homogeneous and provide new insights into the role of fibroblasts in inflammatory pathology. In addition, new molecular insights into the mechanisms of fibroblast activation reveal powerful cell-intrinsic amplification loops that synergize with primary fibroblast stimuli to result in striking responses. In this Review, we focus on recent developments in our understanding of fibroblast heterogeneity and fibroblast pathology across tissues and diseases in rheumatoid arthritis and inflammatory bowel diseases. We highlight new approaches to, and applications of, single-cell profiling techniques and what they teach us about fibroblast biology. Finally, we address how these insights could lead to the development of novel therapeutic approaches to targeting fibroblasts in disease.
Kevin Wei, Hung N. Nguyen, Michael B. Brenner
Neurodegenerative diseases encompass a large group of conditions that are clinically and pathologically diverse yet are linked by a shared pathology of misfolded proteins. The accumulation of insoluble aggregates is accompanied by a progressive loss of vulnerable neurons. For some patients, the symptoms are motor focused (ataxias), while others experience cognitive and psychiatric symptoms (dementias). Among the shared symptoms of neurodegenerative diseases is a disruption of the sleep/wake cycle that occurs early in the trajectory of the disease and may be a risk factor for disease development. In many cases, the disruption in the timing of sleep and other rhythmic physiological markers immediately raises the possibility of neurodegeneration-driven disruption of the circadian timing system. The aim of this Review is to summarize the evidence supporting the hypothesis that circadian disruption is a core symptom within neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, and to discuss the latest progress in this field. The Review discusses evidence that neurodegenerative processes may disrupt the structure and function of the circadian system and describes circadian-based interventions as well as timed drug treatments that may improve a wide range of symptoms associated with neurodegenerative disorders. It also identifies key gaps in our knowledge.
Christopher S. Colwell
Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a unique opportunity for personalized/precision medicine and overall societal well-being. In this Review, we discuss the implications of circadian disruption for human health using a bench-to-bedside approach. Evidence from preclinical and translational science is applied to a clinical and population-based approach. Given the broad implications of circadian regulation for human health, this Review focuses its discussion on selected examples in neurologic, psychiatric, metabolic, cardiovascular, allergic, and immunologic disorders that highlight the interrelatedness between circadian disruption and human disease and the potential of circadian-based interventions, such as bright light therapy and exogenous melatonin, as well as chronotherapy to improve and/or modify disease outcomes.
Anna B. Fishbein, Kristen L. Knutson, Phyllis C. Zee
Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the “balanced” proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.
Peter S. Choi, Andrei Thomas-Tikhonenko
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