All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell’s ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract’s ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases.
Sandip M. Swain, Rodger A. Liddle
First achieved in 1998 by Cole et al., the complete genome sequence of Mycobacterium tuberculosis continues to provide an invaluable resource to understand tuberculosis (TB), the leading cause of global infectious disease mortality. At the 25-year anniversary of this accomplishment, we describe how insights gleaned from the M. tuberculosis genome have led to vital tools for TB research, epidemiology, and clinical practice. The increasing accessibility of whole-genome sequencing across research and clinical settings has improved our ability to predict antibacterial susceptibility, to track epidemics at the level of individual outbreaks and wider historical trends, to query the efficacy of the bacille Calmette-Guérin (BCG) vaccine, and to uncover targets for novel antitubercular therapeutics. Likewise, we discuss several recent efforts to extract further discoveries from this powerful resource.
Benjamin N. Koleske, William R. Jacobs Jr., William R. Bishai
Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care. Within this space is the cardiac macrophage, a key modulator of cardiac function in health and disease. After a myocardial infarction, myeloid macrophages both protect and harm the heart. To varying degrees, such outcomes are a function of myeloid ontogeny and heterogeneity, as well as functional cellular plasticity. Diversity is further shaped by the extracellular milieu, which fluctuates considerably after coronary occlusion. Ischemic limitation of nutrients constrains the metabolic potential of immune cells, and accumulating evidence supports a paradigm whereby macrophage metabolism is coupled to divergent inflammatory consequences, although experimental evidence for this in the heart is just emerging. Herein we examine the heterogeneous cardiac macrophage response following ischemic injury, with a focus on integrating putative contributions of immunometabolism and implications for therapeutically relevant cardiac injury versus cardiac repair.
Edward B. Thorp
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix–secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
James May, Jane A. Mitchell, R. Gisli Jenkins
Antibody-drug conjugates (ADCs) have emerged as a revolutionary therapeutic class, combining the precise targeting ability of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutics. Notably, ADCs have rapidly advanced in the field of breast cancer treatment. This innovative approach holds promise for strengthening the immune system through antibody-mediated cellular toxicity, tumor-specific immunity, and adaptive immune responses. However, the development of upfront and acquired resistance poses substantial challenges in maximizing the effectiveness of these therapeutics, necessitating a deeper understanding of the underlying mechanisms. These mechanisms of resistance include antigen loss, derangements in ADC internalization and recycling, drug clearance, and alterations in signaling pathways and the payload target. To overcome resistance, ongoing research and development efforts are focused on urgently identifying biomarkers, integrating immune therapy approaches, and designing novel cytotoxic payloads. This Review provides an overview of the mechanisms and clinical effectiveness of ADCs, and explores their unique immune-boosting function, while also highlighting the complex resistance mechanisms and safety challenges that must be addressed. A continued focus on how ADCs impact the tumor microenvironment will help to identify new payloads that can improve patient outcomes.
Hannah L. Chang, Blake Schwettmann, Heather L. McArthur, Isaac S. Chan
The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled “Yet to be Charted: Lymphatic System in Health and Disease,” held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field.
Babak J. Mehrara, Andrea J. Radtke, Gwendalyn J. Randolph, Brianna T. Wachter, Patricia Greenwel, Ilsa I. Rovira, Zorina S. Galis, Selen C. Muratoglu
Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.
Feyza Gul Ozbay Kurt, Samantha Lasser, Ihor Arkhypov, Jochen Utikal, Viktor Umansky
Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical protein signatures and abnormal protein depositions that often correlate with disease pathogenesis. Recent evidence indicates that many pathologic proteins assemble into liquid-like protein phases through the highly coordinated process of liquid-liquid phase separation. Over the last decade, biomolecular phase transitions have emerged as a fundamental mechanism of cellular organization. Liquid-like condensates organize functionally related biomolecules within the cell, and many neuropathology-associated proteins reside within these dynamic structures. Thus, examining biomolecular phase transitions enhances our understanding of the molecular mechanisms mediating toxicity across diverse neurodegenerative diseases. This Review explores the known mechanisms contributing to aberrant protein phase transitions in neurodegenerative diseases, focusing on tau and TDP-43 proteinopathies and outlining potential therapeutic strategies to regulate these pathologic events.
Bryan T. Hurtle, Longxin Xie, Christopher J. Donnelly
Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.
Rosa Spinelli, Ritesh Kumar Baboota, Silvia Gogg, Francesco Beguinot, Matthias Blüher, Annika Nerstedt, Ulf Smith
Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well as nonclinical translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. However, a number of tau-targeting therapies with various mechanisms of action have shown little promise in clinical trials in different tauopathies. We review what is known about tau biology, genetics, and therapeutic mechanisms that have been tested in clinical trials to date. We discuss possible reasons for failures of these therapies, such as use of imperfect nonclinical models that do not predict human effects for drug development; heterogeneity of human tau pathologies which may lead to variable responses to therapy; and ineffective therapeutic mechanisms, such as targeting of the wrong tau species or protein epitope. Innovative approaches to human clinical trials can help address some of the difficulties that have plagued our field’s development of tau-targeting therapies thus far. Despite limited clinical success to date, as we continue to refine our understanding of tau’s pathogenic mechanism(s) in different neurodegenerative diseases, we remain optimistic that tau-targeting therapies will eventually play a central role in the treatment of tauopathies.
Niyatee Samudra, Courtney Lane-Donovan, Lawren VandeVrede, Adam L. Boxer
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