Review

Abstract

In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell–derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans. In addition, there has been success in reprogramming developmentally related cell types into β cells. Reprogramming approaches could find therapeutic applications by inducing β cell conversion in vivo or by reprogramming cells ex vivo followed by implantation. Finally, recent studies have revealed novel pharmacologic targets for stimulating β cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual β cells in diabetic patients. Here, we provide an overview of progress made toward β cell replacement and regeneration and discuss promises and challenges for clinical implementation of these strategies.

Authors

Jacqueline R. Benthuysen, Andrea C. Carrano, Maike Sander

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Abstract

Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. In this review, we will summarize our current understanding of the role of HIF-αs in shaping macrophage and neutrophil functions in the pathogenesis and progression of multiple inflammatory diseases.

Authors

Nan Lin, M. Celeste Simon

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Abstract

The extracellular matrix (ECM) is the noncellular component critical in the maintenance of organ structure and the regulation of tissue development, organ structure, and cellular signaling. The ECM is a dynamic entity that undergoes continuous degradation and resynthesis. In addition to compromising structure, degradation of the ECM can liberate bioactive fragments that cause cellular activation and chemotaxis of a variety of cells. These fragments are termed matrikines, and their cellular activities are sentinel in the development and progression of tissue injury seen in chronic lung disease. Here, we discuss the matrikines that are known to be active in lung biology and their roles in lung disease. We also consider the use of matrikines as disease markers and potential therapeutic targets in lung disease.

Authors

Amit Gaggar, Nathaniel Weathington

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Abstract

Kaposi sarcoma–associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus.

Authors

Dirk P. Dittmer, Blossom Damania

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Abstract

HIF1α is a common component of pathways involved in the control of cellular metabolism and has a role in regulating immune cell effector functions. Additionally, HIF1α is critical for the maturation of dendritic cells and for the activation of T cells. HIF1α is induced in LPS-activated macrophages, where it is critically involved in glycolysis and the induction of proinflammatory genes, notably Il1b. The mechanism of LPS-stimulated HIF1α induction involves succinate, which inhibits prolyl hydroxylases (PHDs). Pyruvate kinase M2 (PKM2) is also induced and interacts with and promotes the function of HIF1α. In another critical inflammatory cell type, Th17 cells, HIF1α acts via the retinoic acid–related orphan receptor-γt (RORγt) to drive Th17 differentiation. HIF1α is therefore a key reprogrammer of metabolism in inflammatory cells that promotes inflammatory gene expression.

Authors

Sarah E. Corcoran, Luke A.J. O’Neill

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Abstract

Radiotherapy is an effective treatment strategy for cancer, but a significant proportion of patients experience radiation-induced toxicity due to damage to normal tissue in the irradiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiotherapy is a long-held goal. Hypoxia-inducible factors (HIFs) regulate the production of factors that may protect several cellular compartments affected by radiation-induced toxicity. Pharmacological inhibitors of prolyl hydroxylase domain–containing enzymes (PHDs), which result in stabilization of HIFs, have recently been proposed as a new class of radioprotectors. In this review, radiation-induced toxicity in the gastrointestinal (GI) tract and the main cellular compartments studied in this context will be discussed. The effects of PHD inhibition on GI radioprotection will be described in detail.

Authors

Monica M. Olcina, Amato J. Giaccia

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Abstract

The tumor immune response is in a dynamic balance between antitumor mechanisms, which serve to decrease cancer growth, and the protumor inflammatory response, which increases immune tolerance, cell survival, and proliferation. Hypoxia and expression of HIF-1α and HIF-2α are characteristic features of all solid tumors. HIF signaling serves as a major adaptive mechanism in tumor growth in a hypoxic microenvironment. HIFs represent a critical signaling node in the switch to protumorigenic inflammatory responses through recruitment of protumor immune cells and altered immune cell effector functions to suppress antitumor immune responses and promote tumor growth through direct growth-promoting cytokine production, angiogenesis, and ROS production. Modulating HIF function will be an important mechanism to dampen the tumor-promoting inflammatory response and inhibit cancer growth.

Authors

Daniel Triner, Yatrik M. Shah

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Abstract

Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa-derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease.

Authors

Louise E. Glover, J. Scott Lee, Sean P. Colgan

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Abstract

The role of tumor-associated macrophages (TAMs) in cancer is often correlated with poor prognosis, even though this statement should be interpreted with care, as the effects of macrophages primarily depend on their localization within the tumor. This versatile cell type orchestrates a broad spectrum of biological functions and exerts very complex and even opposing functions on cell death, immune stimulation or suppression, and angiogenesis, resulting in an overall pro- or antitumoral effect. We are only beginning to understand the environmental cues that contribute to transient retention of macrophages in a specific phenotype. It has become clear that hypoxia shapes and induces specific macrophage phenotypes that serve tumor malignancy, as hypoxia promotes immune evasion, angiogenesis, tumor cell survival, and metastatic dissemination. Additionally, TAMs in the hypoxic niches within the tumor are known to mediate resistance to several anticancer treatments and to promote cancer relapse. Thus, a careful characterization and understanding of this macrophage differentiation state is needed in order to efficiently tailor cancer therapy.

Authors

Anne-Theres Henze, Massimiliano Mazzone

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Abstract

The traditional view of genome organization has been upended in the last decade with the discovery of vast amounts of non–protein-coding transcription. After initial concerns that this “dark matter” of the genome was transcriptional noise, it is apparent that a subset of these noncoding RNAs are functional. Long noncoding RNA (lncRNA) genes resemble protein-coding genes in several key aspects, and they have myriad molecular functions across many cellular pathways and processes, including oncogenic signaling. The number of lncRNA genes has recently been greatly expanded by our group to triple the number of protein-coding genes; therefore, lncRNAs are likely to play a role in many biological processes. Based on their large number and expression specificity in a variety of cancers, lncRNAs are likely to serve as the basis for many clinical applications in oncology.

Authors

Joseph R. Evans, Felix Y. Feng, Arul M. Chinnaiyan

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Abstract

The number of long noncoding RNAs (lncRNAs) has grown rapidly; however, our understanding of their function remains limited. Although cultured cells have facilitated investigations of lncRNA function at the molecular level, the use of animal models provides a rich context in which to investigate the phenotypic impact of these molecules. Promising initial studies using animal models demonstrated that lncRNAs influence a diverse number of phenotypes, ranging from subtle dysmorphia to viability. Here, we highlight the diversity of animal models and their unique advantages, discuss the use of animal models to profile lncRNA expression, evaluate experimental strategies to manipulate lncRNA function in vivo, and review the phenotypes attributable to lncRNAs. Despite a limited number of studies leveraging animal models, lncRNAs are already recognized as a notable class of molecules with important implications for health and disease.

Authors

Michael Feyder, Loyal A. Goff

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Abstract

Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease.

Authors

Cormac T. Taylor, Glen Doherty, Padraic G. Fallon, Eoin P. Cummins

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Abstract

The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care. Ongoing studies using advanced molecular and immunological tools along with improved clinical classification show that severe asthma does not identify a specific patient phenotype, but rather includes patients with constant medical needs, whose pathobiologic and clinical characteristics vary widely. Accordingly, in recent clinical trials, therapies guided by specific patient characteristics have had better outcomes than previous therapies directed to any subject with a diagnosis of severe asthma. However, there are still significant gaps in our understanding of the full scope of this disease that hinder the development of effective treatments for all severe asthmatics. In this Review, we discuss our current state of knowledge regarding severe asthma, highlighting different molecular and immunological pathways that can be targeted for future therapeutic development.

Authors

Anuradha Ray, Mahesh Raundhal, Timothy B. Oriss, Prabir Ray, Sally E. Wenzel

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Abstract

A major subset of human cancers shows evidence for spontaneous adaptive immunity, which is reflected by the presence of infiltrating CD8+ T cells specific for tumor antigens within the tumor microenvironment. This observation has raised the question of which innate immune sensing pathway might detect the presence of cancer and lead to a natural adaptive antitumor immune response in the absence of exogenous infectious pathogens. Evidence for a critical functional role for type I IFNs led to interrogation of candidate innate immune sensing pathways that might be triggered by tumor presence and induce type I IFN production. Such analyses have revealed a major role for the stimulator of IFN genes pathway (STING pathway), which senses cytosolic tumor–derived DNA within the cytosol of tumor-infiltrating DCs. Activation of this pathway is correlated with IFN-β production and induction of antitumor T cells. Based on the biology of this natural immune response, pharmacologic agonists of the STING pathway are being developed to augment and optimize STING activation as a cancer therapy. Intratumoral administration of STING agonists results in remarkable therapeutic activity in mouse models, and STING agonists are being carried forward into phase I clinical testing.

Authors

Leticia Corrales, Sarah M. McWhirter, Thomas W. Dubensky Jr., Thomas F. Gajewski

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Abstract

Malaria remains a global public health threat, with half of the world’s population at risk. Despite numerous efforts in the past decade to develop new antimalarial drugs to surmount increasing resistance to common therapies, challenges remain in the expansion of the current antimalarial arsenal for the elimination of this disease. The requirement of prophylactic and radical cure activities for the next generation of antimalarial drugs demands that new research models be developed to support the investigation of the elusive liver stage of the malaria parasite. In this Review, we revisit current antimalarial therapies and discuss recent advances for in vitro and in vivo malaria research models of the liver stage and their importance in probing parasite biology and the discovery of novel drug candidates.

Authors

Rene Raphemot, Dora Posfai, Emily R. Derbyshire

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Abstract

Immune cell metabolism is dynamically regulated in parallel with the substantial changes in cellular function that accompany immune cell activation. While these changes in metabolism are important for facilitating the increased energetic and biosynthetic demands of activated cells, immune cell metabolism also has direct roles in controlling the functions of immune cells and shaping the immune response. A theme is emerging wherein nutrients, metabolic enzymes, and metabolites can act as an extension of the established immune signal transduction pathways, thereby adding an extra layer of complexity to the regulation of immunity. This Review will outline the metabolic configurations adopted by different immune cell subsets, describe the emerging roles for metabolic enzymes and metabolites in the control of immune cell function, and discuss the therapeutic implications of this emerging immune regulatory axis.

Authors

Nadine Assmann, David K. Finlay

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Abstract

RNA is likely to be the most rediscovered macromolecule in biology. Periodically, new non-canonical functions have been ascribed to RNA, such as the ability to act as a catalytic molecule or to work independently from its coding capacity. Recent annotations show that more than half of the transcriptome encodes for RNA molecules lacking coding activity. Here we illustrate how these transcripts affect skeletal muscle differentiation and related disorders. We discuss the most recent scientific discoveries that have led to the identification of the molecular circuitries that are controlled by RNA during the differentiation process and that, when deregulated, lead to pathogenic events. These findings will provide insights that can aid in the development of new therapeutic interventions for muscle diseases.

Authors

Monica Ballarino, Mariangela Morlando, Alessandro Fatica, Irene Bozzoni

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Abstract

Neutrophil extracellular traps (NETs) were discovered as extracellular strands of decondensed DNA in complex with histones and granule proteins, which were expelled from dying neutrophils to ensnare and kill microbes. NETs are formed during infection in vivo by mechanisms different from those originally described in vitro. Citrullination of histones by peptidyl arginine deiminase 4 (PAD4) is central for NET formation in vivo. NETs may spur formation of autoantibodies and may also serve as scaffolds for thrombosis, thereby providing a link among infection, autoimmunity, and thrombosis. In this review, we present the mechanisms by which NETs are formed and discuss the physiological and pathophysiological consequences of NET formation. We conclude that NETs may be of more importance in autoimmunity and thrombosis than in innate immune defense.

Authors

Ole E. Sørensen, Niels Borregaard

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Abstract

Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A multiprotein complex known as shelterin prevents recognition of telomeric sequences as sites of DNA damage. Telomere erosion contributes to human diseases ranging from BM failure to premature aging syndromes and cancer. The role of shelterin telomere protection is less understood. Mutations in genes encoding the shelterin proteins TRF1-interacting nuclear factor 2 (TIN2) and adrenocortical dysplasia homolog (ACD) were identified in dyskeratosis congenita, a syndrome characterized by somatic stem cell dysfunction in multiple organs leading to BM failure and other pleiotropic manifestations. Here, we introduce the biochemical features and in vivo effects of individual shelterin proteins, discuss shelterin functions in hematopoiesis, and review emerging knowledge implicating the shelterin complex in hematological disorders.

Authors

Morgan Jones, Kamlesh Bisht, Sharon A. Savage, Jayakrishnan Nandakumar, Catherine E. Keegan, Ivan Maillard

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Abstract

Although the use of antioxidants for the treatment of cancer and HIV/AIDS has been proposed for decades, new insights gained from redox research have suggested a very different scenario. These new data show that the major cellular antioxidant systems, the thioredoxin (Trx) and glutathione (GSH) systems, actually promote cancer growth and HIV infection, while suppressing an effective immune response. Mechanistically, these systems control both the redox- and NO-based pathways (nitroso-redox homeostasis), which subserve innate and cellular immune defenses. Dual inhibition of the Trx and GSH systems synergistically kills neoplastic cells in vitro and in mice and decreases resistance to anticancer therapy. Similarly, the population of HIV reservoir cells that constitutes the major barrier to a cure for AIDS is exquisitely redox sensitive and could be selectively targeted by Trx and GSH inhibitors. Trx and GSH inhibition may lead to a reprogramming of the immune response, tilting the balance between the immune system and cancer or HIV in favor of the former, allowing elimination of diseased cells. Thus, therapies based on silencing of the Trx and GSH pathways represent a promising approach for the cure of both cancer and AIDS and warrant further investigation.

Authors

Moran Benhar, Iart Luca Shytaj, Jonathan S. Stamler, Andrea Savarino

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