Commentary
Abstract
Microglia play critical roles in immune defense within the central nervous system (CNS), and microglia-mediated immune changes in the brain are observed in various neurodegenerative diseases, including Parkinson’s disease (PD). While PET imaging with a range of radiolabeled ligands has been invaluable for visualizing and quantifying neuroimmune changes in the brains of patients with PD, no PET ligands currently exist that are specific to microglia. In this issue of the JCI, Mills et al. used the PET radioligand [¹¹C]CPPC to image colony stimulating factor 1 receptor (CSF1R), revealing a connection between increased CSF1R expression and microglia-mediated brain immune changes in patients with PD. The study demonstrated that elevated CSF1R expression colocalized with a microglial-specific marker in brain regions vulnerable to PD. Moreover, quantifying CSF1R density with [¹¹C]CPPC-PET imaging in living brains may provide an indicator of motor and cognitive impairments in the early stages of PD. These findings underscore the potential of CSF1R-PET imaging as a microglial-sensitive biomarker of brain immune function in PD.
Authors
So Jeong Lee, Changning Wang, Jacob Hooker
Abstract
The effect of food intake patterns on growth remain largely unknown. In this issue of the JCI, Hornsby et al. provide compelling evidence that, in young males, confining food intake to three meals a day entrains preprandial ghrelin release, leading to postprandial growth hormone pulse release that is associated with an increase in epiphysial plate expansion — a measure indicative of increased bone growth. The positive effects of discrete meal intake, on bone, was dependent on an intact ghrelin signaling system. This Commentary posits that meal-entrained ghrelin release may enhance skeletal accrual, whether through direct action on bone cells, via stimulation of growth hormone secretion, or in concert with other nutrient-responsive hormones. Coordinating these hormonal cues with food intake could maximize bone acquisition and improve bone health throughout the lifespan.
Authors
Rhonda D. Kineman, Shoshana Yakar
Abstract
B cell depletion is a highly effective therapy in multiple sclerosis (MS), reducing inflammation and restoring immune balance. In this issue of the JCI, Wei et al. used single-cell RNA-Seq and flow cytometry, identifying the comprehensive effects of B cell depletion on the immune response, including an increase in antiinflammatory cerebrospinal fluid macrophages and elevated TNF-α expression by peripheral CD16+ monocytes. The authors also detected shifts in T cell populations that resulted in reduced myelin-reactive CD4+ T cells and the expansion of TIGIT+ Tregs. The findings uncover immunoregulatory mechanisms and suggest therapeutic strategies for MS and other autoimmune disorders.
Authors
Carolina M. Polonio, Francisco J. Quintana
Abstract
Hypertension is a leading cause of morbidity and mortality, with pathologic consequences on multiple end-organ systems. Smooth muscle plasticity and its epigenetic regulation promote disease pathogenesis, but the genetic levers that control such activity are incompletely defined. In this issue of the JCI, Mangum et al. utilized high-density genomic data to define the causal and pathogenic role of a variant at the JMJD3 locus — one that is associated with systolic blood pressure and governs an allele-specific molecular mechanism controlling smooth muscle behavior in hypertension. These findings have clinical implications relevant to patient risk stratification and personalized therapeutics.
Authors
Lloyd D. Harvey, Stephen Y. Chan
Abstract
Fanconi anemia (FA) is the most common inherited bone marrow failure disorder, caused by pathogenic variants in genes involved in the FA DNA repair pathway. In this issue of the JCI, two studies report three germline homozygous loss-of-function variants in FAAP100, a key component of the FA core complex, identified in three unrelated families. These variants result in severe developmental phenotypes that are among the most extreme reported in FA to date. Harrison et al. described individuals from two families with recurrent pregnancy loss and neonatal death due to homozygous FAAP100 frameshift and truncating variants, respectively. Kuehl et al. identified a homozygous missense variant in a fetus with congenital malformations consistent with FA. Collectively, both studies provide robust functional evidence from ex vivo and in vitro assays with animal models supporting the pathogenicity of these variants and establish FAAP100 as a causative FA gene.
Authors
Claire C. Homan, Hamish S. Scott, Parvathy Venugopal
Abstract
Cell plasticity is a hallmark of cancer, enabling tumor cells to acquire multiple phenotypes responsible for tumor progression, metastasis, and therapy resistance. In this issue of the JCI, Kawai and colleagues leveraged genetically engineered mouse models (GEMM) of pancreatic ductal adenocarcinoma (PDAC) to demonstrate that loss of Pbrm1, a member of the SWI/SNF complex, drives dedifferentiation and aggressive tumor features. Pbrm1 loss activated a program of epithelial-to-mesenchymal transition (EMT) and allowed the emergence of poorly differentiated histologies that are commonly associated with high recurrence rate and dismal prognosis. These findings reveal the role of the SWI/SNF complex during PDAC evolution in maintaining cell identity and restraining the progression of this lethal disease.
Authors
Luigi Perelli, Giannicola Genovese
Abstract
Accumulating evidence from rodent and human studies indicates that the activity of thermogenic adipocytes positively correlates with optimal metabolic function. In this issue of the JCI, Yesian et al. uncover a paracrine signaling pathway from type 2 innate lymphoid cells to preadipocytes via IL-13 that increases beige adipogenesis through a PPARγ-dependent pathway. Mice with deletion of Il13ra1 demonstrated glucose dysregulation, and variants near the human IL13RA1 locus were associated with body weight and diabetic status. It is tempting to speculate that targeting IL-13 holds therapeutic potential for improving metabolic fitness in humans.
Authors
Margo P. Emont, Jun Wu
Abstract
Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, pose challenges due to their complex pathophysiology and high prevalence. Despite advances in immune-targeted therapies, a substantial number of patients fail to achieve mucosal healing, highlighting the need for alternative therapeutic strategies. In this issue of the JCI, D’Addio et al. identified another mechanism underlying impaired epithelial regeneration in Crohn’s disease. They found that abnormal cell death in intestinal epithelial stem cells, mediated by altered TMEM219 signaling, led to impaired mucosal healing. Targeting TMEM219 with ecto-TMEM219, which blocks its activation, restored stem cell function and promoted mucosal healing in vitro and in vivo. These findings suggest a promising therapeutic avenue focusing on epithelial repair. Additionally, patient-derived organoids (PDOs) emerge as a valuable tool for personalized treatment strategies and for advancing the field of IBD research. This study underscores the importance of epithelial cell biology in developing innovative IBD therapies.
Authors
Nicolas Schlegel
Abstract
Acute kidney injury (AKI) is a frequent complication in critically ill patients and triggers a systemic inflammatory response that can contribute to lung injury, ultimately worsening clinical outcomes. However, diagnostic and therapeutic strategies remain unavailable. In this issue of the JCI, Komaru et al. explored leukocyte trafficking and vascular pooling following AKI in mice as an underlying mechanism of acute lung injury. Using intravital microscopy, the authors observed rapid accumulation of neutrophils in pulmonary capillaries within minutes of AKI onset. These neutrophils followed monocytes and slowed blood flow. Notably, disruption of this process improved oxygenation. The findings provide insights into this complex inter-organ crosstalk and open avenues for future research.
Authors
Ulrich Matt, Susanne Herold
Abstract
IgA nephropathy (IgAN) is a highly prevalent type of primary glomerulonephritis. IgAN involves mesangial deposition of immune complexes leading to complement activation, inflammation, and glomerular injury. A key hit for pathogenesis involves aberrant O-glycosylation in the hinge region of IgA. Despite its prevalence, however, the mechanisms underlying IgAN remain incompletely understood. In this issue of the JCI, Prakash and colleagues used whole-exome sequencing of two IgAN probands to identify loss-of-function variants in GALNT14 leading to loss of the enzyme GalNAc-T14, which is involved in O-glycosylation. The authors then performed a classical bedside-to-bench investigation using a Galnt14–/– mouse model and connected loss of GalNAc-T14 to excess IgA production, impaired B lymphocyte homing, and defective intestinal mucus production. These findings build a more unified understanding of IgAN pathogenesis from defective O-glycosylation with loss-of-function variants in GALNT14.
Authors
John Pell, Madhav C. Menon
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