Parathyroid hormone (PTH) has complex effects on bone, including stimulating bone formation and regulating the hematopoietic stem cell (HSC) niche. In the current issue of the JCI, Li et al. demonstrated that the microbiome, through the production of short-chain fatty acids and in particular, butyrate, is necessary for the ability of PTH to increase osteoblast numbers and stimulate bone formation. In addition to implications for the treatment of osteoporosis with PTH analogs, this pathway may be part of a broader mechanism through which the microbiome serves its key function of modulating the immune system.
Tregs require specific epigenetic signatures to induce and maintain their suppressive function in the context of inflammation and cancer surveillance. In this issue of the JCI, Xiong and colleagues identify a critical role for the epigenetic repressor REST corepressor 1 (CoREST) in promoting Treg suppressive transcriptional and functional programs. Pharmacologic inhibition and genetic loss of CoREST in Tregs impaired organ allograft tolerance and unleashed antitumor immunity via epigenetic activation of effector T cell programs. We propose that exploiting epigenetic control mechanisms will further the translation of Treg-based therapeutics to target inflammatory and malignant disorders.
Luisa Morales-Nebreda, Kathryn A. Helmin, Benjamin D. Singer
Currently, the incidence of HIV infection exceeds the death rate from HIV, and as a result, the prevalence of individuals living with the infection continues to increase. A critical limitation preventing the development of curative strategies is the lack of knowledge regarding mechanisms that allow HIV-infected cells to persist in individuals during combination antiviral therapy (ART). In this issue of the JCI, Chaillon and coworkers assessed HIV-infected cells from various anatomic compartments obtained through a rapid autopsy program of individuals undergoing long-term ART. This study, made possible with strong community collaboration, provides new insights on the potential locations of reservoirs of HIV-infected cells that persist during therapy.
The cardiomyopathy of Duchenne muscular dystrophy (DMD) is an important cause of morbidity and mortality in affected males with this dreaded muscle disease. Previous studies have implicated changes in expression and subcellular localization of connexin-43 (Cx43), the major ventricular gap junction protein, in DMD cardiomyopathy. In this issue of the JCI, Himelman et al. explore how hypophosphorylation of Cx43 at a triplet of serine residues (S325/S328/S330) in the regulatory C-terminus contributes to multiple features of the cardiomyopathy phenotype. Using a mouse model of DMD cardiomyopathy in which phosphomimetic glutamic acids are substituted for serines at these residues in Cx43, Himelman et al. observed reduced gap junction remodeling and lateralization of Cx43 immunosignals, protection against isoproterenol-induced arrhythmias, and improved Ca2+ homeostasis. This study contributes to the understanding of pathologic Cx43 remodeling and encourages further research into developing strategic interventions to mitigate cardiac dysfunction and arrhythmias in DMD patients.
Robin M. Shaw, Jeffrey E. Saffitz
The ATP-sensitive K+ channel (KATP) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.x or SUR mutations result in KATP channelopathies, which reflect the physiological roles of these channels, including but not limited to insulin secretion, cardiac protection, and blood flow regulation. In this issue of the JCI, McClenaghan et al. explored one of the channelopathies, namely Cantu syndrome (CS), which is a result of one kind of KATP channel mutation. Using a knockin mouse model, the authors demonstrated that gain-of-function KATP mutations in vascular smooth muscle resulted in cardiac remodeling. Moreover, they were able to reverse the cardiovascular phenotypes by administering the KATP channel blocker glibenclamide. These results exemplify how genetic mutations can have an impact on developmental trajectories, and provide a therapeutic approach to mitigate cardiac hypertrophy in cases of CS.
Guiling Zhao, Aaron Kaplan, Maura Greiser, W. Jonathan Lederer
Mosquito-transmitted Plasmodium falciparum infection can cause human cerebral malaria (HCM) with high mortality rates. The abundance of infected red blood cells that accumulate in the cerebral vasculature of patients has led to the belief that these brain-sequestered cells solely cause pathogenesis. However, animal models suggest that CD8+ T cells migrate to and accumulate in the brain, directly contributing to experimental cerebral malaria (ECM) mortality. In this issue of the JCI, Riggle et al. explored the brain vasculature from 34 children who died from HCM or other causes and frequently found CD3+ CD8+ T cells in contact with endothelial cells. Further, the authors show that coinfection with HIV enhanced such CD3+ CD8+ T cell luminal distribution. These findings suggest that the mouse model for cerebral malaria may accurately reflect human disease pathology. This study sheds new light on the mechanisms behind blood-brain barrier breakdown in this complicated neurological disease and opens up alternative approaches for treatment.
Laurent Rénia, Georges E.R. Grau, Samuel C. Wassmer
The rapid rise in circulating fibroblast growth factor 23 (FGF23) associated with kidney injury results in calcitriol deficiency, altered calcium homeostasis, and secondary hyperparathyroidism, and may contribute to cardiovascular complications and death. However, the mechanisms of increased FGF23 in states of kidney injury remain unclear. In this issue of the JCI, Simic et al. screened plasma taken from the renal vein of patients undergoing cardiac catheterization and identified glycerol-3-phosphate (G-3-P) as the most significant correlate of simultaneous arterial FGF23 levels. When G-3-P was administered to mice, FGF23 production increased in bone. In a series of elegant mouse studies, the authors discovered a pathway linking increased G-3-P to increased FGF23 via increases in lysophosphatidic acid (LPA), which activates the LPA receptor 1 in FGF23-secreting cells in the bone and bone marrow. Although the authors present human data that broadly support the results from the mouse models, further research is needed to determine whether targeting the G-3-P/FGF23 pathway has the potential to modify FGF23-related complications in the clinic.
Alexander Grabner, Myles Wolf
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease with heterogeneous constitutional and neurological complaints. Infection-like symptoms often herald disease onset, but no pathogen or immune defect has been conclusively linked. In this issue of the JCI, Mandarano et al. illuminate bioenergetic derangements of ME/CFS T cell subsets. CD4+ and CD8+ T cells had impaired resting glycolysis. CD8+ cells additionally showed activation-related metabolic remodeling deficits and decreased mitochondrial membrane potential; a subset had increased resting mitochondrial mass. Immune senescence and exhaustion paradigms offer only partial explanations. Hence, unique mechanisms of disrupted immunometabolism may underlie the complex neuroimmune dysfunction of ME/CFS.
Chikungunya virus (CHIKV) is an emerging arbovirus, endemic in many parts of the world, that is spread by travelers and adapts to new mosquito vectors that live in temperate climates. CHIKV replicates in many host tissues and initially causes a self-limiting febrile illness similar to dengue. However, in 30%–40% of cases, CHIKV also causes long-term painful and debilitating muscle and joint pain, the pathogenesis of which remains unknown. In this issue of the JCI, Lentscher et al. engineered a skeletal muscle–restricted CHIKV to show that while musculoskeletal disease requires viral replication in affected muscle, muscular pathology is mediated by host immunological factors. These findings de-link viral replication and disease symptoms, illuminate the virus-host interplay in CHIKV symptomatology, and raise the possibility that immune modulation is a therapeutic option. The results also highlight possible solutions to existing vaccine barriers and provide insights that may apply to other viral diseases.
Aneurysms are common in the abdominal and thoracic regions of the aorta and can cause death due to dissection or rupture. Traditionally, thoracic aortic aneurysms have been labeled as a degenerative disease, characterized by alterations in extracellular matrix and loss of smooth muscle cells (SMCs) in the medial layer of the aortic wall. In this issue of the JCI, Li and colleagues introduce an unconventional concept by demonstrating that mTOR-dependent proliferative SMCs render the aortic wall vulnerable to dilatation and dissection rather than prevent disease progression. These vascular SMCs, termed degradative SMCs, compromise the medial properties and function of the aortic wall by enhanced proteolytic and phagocytic activity; however, the cells do not transdifferentiate into macrophages. The degradative SMC phenotype also worsens atherosclerotic disease and could thus be considered as a therapeutic target for diverse aortic diseases.
Maarten Hulsmans, Matthias Nahrendorf
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