Commentary
Abstract
Pain is a serious medical condition with current treatments remaining limited by side effects. The Nav1.7 voltage-gated sodium channel is a crucial determinant of nociceptor excitability and a promising target for nonaddictive analgesics. However, development of blockers has been difficult. In this issue of the JCI, Singh, Bernabucci, and authors identify a strategy for reducing Nav1.7 currents. These findings identify fibroblast growth factor 13 (FGF13), a homologous factor distinct from typical growth factors (also known as FHF2B), which ramps up Nav1.7, nociceptor excitability, and pain. Compound PW164 was identified as a selective FGF13-Nav1.7 attenuator with analgesic activity. These findings highlight the power of targeting intrinsic modulators of Nav1.7 for pain management.
Authors
Theodore R. Cummins
Abstract
Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15). In this issue of the JCI, Maillard et al. identified NUDT5 as a determinant of TP pharmacology. They demonstrated that loss of NUDT5 conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically, NUDT5 expression variants were associated with altered TP tolerance. These findings position NUDT5 as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.
Authors
Leo Kager, Kaan Boztug
Abstract
T cell–mediated rejection (TCMR) develops after alloantigen-primed T cells migrate into an allograft to cause tissue damage. In contrast to antibody-mediated rejection, which creates lesions in the graft vasculature, injury to the graft vasculature is often limited during TCMR. In this issue of the JCI, Barba et al. investigated the mechanism by which the endothelium is spared from harm caused by graft-infiltrating CD8+ T cells. Endothelial cell protection was due to cell-extrinsic chemokine variations in the environment, rather than cell-intrinsic differences between endothelial and interstitial cells. The CXCL12 gradient in particular facilitated CD8+ T cell movement through the endothelial layer into the graft parenchyma. These findings suggest that targeting the CXCL12 pathway may prevent or alleviate TCMR.
Authors
Scott M. Krummey, Jonathan S. Bromberg
Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, presents a clinical challenge in developing effective treatment options. In this issue of the JCI, Zeng et al. demonstrate a provocative and promising therapeutic strategy for TNBC by leveraging the metabolic vulnerabilities presented by methylthioadenosine phosphorylase (MTAP) deletion to genotoxic stress inducers, such as poly (ADP-ribose) polymerase inhibitors (PARPi). They found that combining MTAP deletion or inhibition with PARPi was highly effective in brain metastatic TNBC where the methionine-limited environment further enhanced this combination. This approach underscores the importance of targeting metabolic vulnerabilities in the development of personalized cancer therapies.
Authors
Samyuktha Suresh, James M. Ford
Abstract
Recent studies have highlighted a possible role for gut microbiota in modulating Alzheimer’s disease pathology, particularly through the actions of gut-derived metabolites and their influence on the immune system. In this issue of the JCI, Chandra et al. reveal that circulating levels of the gut microbiota–derived metabolite propionate affected amyloid burden and glial activation in a mouse model of Aβ amyloidosis. The study also identifies a mechanism for the therapeutic benefit of propionate supplementation, showing that propionate lowered peripheral IL-17 and suppressed Th17 cell activity. These results support the idea of therapeutic targeting of the gut/brain/immune axis, particularly via modulation of Th17 responses, and suggest translational strategies involving microbiome-based or immunological interventions for dementia prevention and treatment.
Authors
Wade K. Self, David M. Holtzman
Abstract
Bardet-Biedl syndrome (BBS) is a complex genetic condition that can affect multiple organ systems, frequently causing pigmentary retinopathy, renal abnormalities, polydactyly, and obesity. Metabolic disturbances including obesity, unsuppressed appetite, and an increased risk of type 2 diabetes (T2D) present clinical management challenges. In this issue of the JCI, Singh et al. present a mouse model of a specific BBS subtype with genetic deletion of the Bbs5 gene. The model recapitulates many of the clinical features observed in patients living with BBS5 and sheds light on adipocyte biology, as well as the hypothalamic mechanisms driving hunger- and food-seeking behaviors that fuel the adverse metabolic phenotype. Importantly, exogenous GLP-1 receptor agonist treatment suppressed both appetite and weight, opening opportunities for direct translation into the clinical setting.
Authors
Jeremy W. Tomlinson
Abstract
Uromodulin is the most abundant protein in human urine, playing diverse roles, from providing frontline defense against uropathogens to regulating electrolyte balance via modulation of ion channels and cotransporters. In this issue of the JCI, Nanamatsu et al. unveil an alternatively spliced isoform of uromodulin that was dynamically induced in response to oxidative stress and tubular injury. Unlike the canonical secreted form, this isoform was retained in the cell, where it interacted with solute carrier proteins primarily localized to the mitochondrial membrane. Through these interactions, it modulated mitochondrial energetics and enhanced tubular cell resilience to injury. These findings broaden our understanding of uromodulin’s multifaceted functions, uncover an adaptive mechanism by which the kidney responds to cellular stress, and open avenues for therapeutic strategies targeting kidney injury and repair.
Authors
Ronak Lakhia, Chunzi Song, Vishal Patel
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
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