The genetic, epigenetic, and environmental etiologic basis of congenital heart disease (CHD) for most heart anomalies remains unexplained. In this issue of the JCI, Lahm et al. performed the largest genome-wide association study (GWAS) to date of European individuals with CHD and clinical subtypes. The comprehensive meta-analysis included over 4000 patients and 8000 controls and uncovered common genetic variants that associated with cardiac anomalies. Lahm and colleagues performed single-cell analysis of induced pluripotent stem cells and heart cells, revealing a role for MACROD2, GOSR2, WNT3, and MSX1 in the developing heart. This study advances our understanding of the genetic basis of common forms of CHD.
DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.
Jung-Hyun Kim, Liping Li, Linda M.S. Resar
Vascular dysfunction resulting in compromised blood-brain barrier (BBB) integrity is evident in aging and disease. Although the complement C3a/C3a receptor (C3a/C3aR) axis influences normal brain aging and disease progression, the mechanisms governing endothelial C3aR–mediated neurovascular inflammation and BBB permeability remain unexplored. In this issue of the JCI, Propson et al. investigated endothelial C3a/C3aR signaling in normal, aged, and neurodegenerative mouse models. Endothelial C3aR signaling modulated age-dependent increases in VCAM1, initiated peripheral lymphocyte infiltration, and enhanced microglial activity. Increased calcium release downstream of C3aR signaling disrupted the vascular endothelial cadherin (VE-cadherin) junctions, increased BBB permeability, and degraded vascular structure and function. Mice lacking C3aR (C3ar1–/–) and mice treated with a C3aR antagonist showed attenuated age-related microglial reactivity and neurodegeneration. These results confirm that complement-mediated signaling impacts vascular health and BBB function in normal aging and neurodegenerative disease, suggesting that complement inhibitors represent a therapeutic option for cerebral microvascular dysfunction.
Kanchan Bhatia, Saif Ahmad, Adam Kindelin, Andrew F. Ducruet
While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.
Kartik Sehgal, David A. Barbie
Mutations in the gene that codes for lamin A/C (LMNA) are a common cause of adult-onset cardiomyopathy and heart failure. In this issue of the JCI, Guénantin and Jebeniani et al. identify impaired cardiomyocyte development and maturation as a prenatal feature in a model of laminopathy. Cardiomyocytes carrying the Lmna point mutation H222P misexpressed genes involved in the epithelial-mesenchymal transition and showed decreased methylation at the fourth lysine of histone H3 (H3K4). Notably, inhibiting lysine-specific demethylase 1 in the LMNA H222P mouse model treated this congenital form of cardiomyopathy and improved survival in utero. These data highlight early epigenomic modifications in lamin A/C-mediated pathology and indicate a unique therapeutic strategy for cardiomyopathy.
Jamie R. Johnston, Daniel F. Selgrade, Elizabeth M. McNally
The neuronal mechanisms that establish 24-hour rhythms in feeding and metabolism remain incompletely understood. In this issue of the JCI, Adlanmerini and colleagues explored the relationship between temporal and homeostatic control of energy balance by focusing on mice that lacked the genes encoding the clock repressor elements REV-ERBα and –β, specifically in the tuberal hypothalamus. Notably, the clock transcription cycle mediated intraneuronal response to the adipostatic hormone leptin. These results show that REV-ERBα and –β in the hypothalamus are necessary for maintaining leptin responsiveness and metabolic homeostasis and lay the foundation to explore how transcriptional changes may link energy-sensing cell types with day/night rhythms. Such information may lead to therapeutics that alleviate the adverse effects of chronic shift work.
Jonathan Cedernaes, Joseph Bass
The success of tumor immunotherapy, while partial, confirms the existence and importance of tumor immunosurveillance. CD8+ T cell recognition of tumor-specific peptides bound to MHC class I (MHC-I) molecules is central to this process. In this issue of the JCI, Fang, Wang, et al. describe a unique tumor immunoevasion strategy based on endocytosis and degradation of MHC-I complexes mediated by the trafficking factor MAL2. Notably, MAL2 expression was associated with poor prognosis of breast cancer, and its downregulation enhanced CD8+ T cell recognition of breast cancer in various experimental models. This work demonstrates that a deeper understanding of tumor interference with MHC-I stability and trafficking has considerable potential for enhancing immunotherapies.
Devin Dersh, Jonathan W. Yewdell
Megakaryocytes (MKs) give rise to platelets, which are blood cells that are essential to prevent hemorrhage. Although the majority of MKs localize to the bone marrow, there is a distinct population of lung-residing MKs (MKL). In this issue of the JCI, Pariser et al. examined gene expression patterns of MKs collected from murine and nonhuman primate bone marrow or lung. This Commentary explores the premise that environmental factors from the lung determine the genetic and phenotypic similarity of MKL to lung dendritic cells, distinguishing MKL from bone marrow MKs. Indeed, while MKL retain the ability to make platelets, they also process and present antigens that activate CD4+ lymphocytes. These data suggest that MKL may play an important role in immune processes beyond platelet production.
Eric Boilard, Kellie R. Machlus
A number of COVID-19 vaccine candidates have shown promising results, but substantial uncertainty remains regarding their effectiveness and global roll-out. Boosting innate immunity with Bacillus Calmette Guerin (BCG) or other live attenuated vaccines may also play a role in the fight against the COVID-19 pandemic. BCG has long been known for its non-specific beneficial effects, most likely explained by epigenetic and metabolic reprogramming of innate immune cells, termed trained immunity. In this issue of the JCI, Rivas et al. add to these arguments by showing that BCG-vaccinated healthcare providers from a Los Angeles healthcare organization had less COVID-19 diagnosis and serology, compared to unvaccinated individuals. Prospective clinical trials are thus warranted to explore BCG effects in COVID-19. We posit that beyond COVID-19, vaccines that elicit trained immunity, such as the BCG, may mitigate the impact of emerging pathogens in future pandemics.
Mihai G. Netea, Jos W.M. van der Meer, Reinout van Crevel
The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID 19, some have questioned whether exposure to seasonal common cold coronaviruses (CCCs) could provide tangible protection against SARS-CoV-2 infection or disease. In this issue of the JCI, Sager, et al. examined SARS-CoV-2 infections and outcomes from patients previously tested for CCC as part of a comprehensive respiratory panel using PCR and were segregated into negative (CCC–) or positive (CCC+) exposure. No differences were seen between groups in terms of susceptibility to SARS-CoV-2 infection. However, hospitalized patients with a documented history of CCC+ infection had lower rates of ICU admissions and higher rates of survival than hospitalized CCC– patients. While these findings are associative and not causative, they highlight evidence suggesting that previous CCC+ infection may influence the disease course of SARS-CoV-2 infection.
David K. Meyerholz, Stanley Perlman
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