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Commentary

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IL-13 priming in precursors drives beige adipogenesis and enhances metabolic homeostasis
Margo P. Emont, Jun Wu
Margo P. Emont, Jun Wu
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e191361. https://doi.org/10.1172/JCI191361.
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IL-13 priming in precursors drives beige adipogenesis and enhances metabolic homeostasis

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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

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Promoting mucosal healing by targeting TMEM219-dependent intestinal epithelial stem cell defects in inflammatory bowel disease
Nicolas Schlegel
Nicolas Schlegel
Published May 15, 2025
Citation Information: J Clin Invest. 2025;135(10):e192640. https://doi.org/10.1172/JCI192640.
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Promoting mucosal healing by targeting TMEM219-dependent intestinal epithelial stem cell defects in inflammatory bowel disease

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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

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Traffic jam in lung capillaries: inter-organ communication impedes gas exchange after acute kidney injury
Ulrich Matt, Susanne Herold
Ulrich Matt, Susanne Herold
Published May 15, 2025
Citation Information: J Clin Invest. 2025;135(10):e192917. https://doi.org/10.1172/JCI192917.
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Traffic jam in lung capillaries: inter-organ communication impedes gas exchange after acute kidney injury

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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

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GALNT14 deficiency: connecting multiple links in the IgA nephropathy pathogenetic chain
John Pell, Madhav C. Menon
John Pell, Madhav C. Menon
Published May 15, 2025
Citation Information: J Clin Invest. 2025;135(10):e192687. https://doi.org/10.1172/JCI192687.
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GALNT14 deficiency: connecting multiple links in the IgA nephropathy pathogenetic chain

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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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Endothelial dysfunction in patients with type 2 diabetes: the truth is in the blood
Sarah Costantino, … , Shafeeq A. Mohammed, Francesco Paneni
Sarah Costantino, … , Shafeeq A. Mohammed, Francesco Paneni
Published May 15, 2025
Citation Information: J Clin Invest. 2025;135(10):e193128. https://doi.org/10.1172/JCI193128.
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Endothelial dysfunction in patients with type 2 diabetes: the truth is in the blood

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Abstract

Endothelial dysfunction remains a cornerstone of diabetic vascular complications. RBCs emerge as pivotal players in endothelial dysfunction, yet the underlying mechanisms remain elusive. In this issue of the JCI, Collado et al. show that the detrimental action of RBCs on the endothelium is mediated by extracellular vesicles (EVs). EVs derived from RBCs (RBC-EVs) of patients with diabetes were taken up by the endothelium and were able to impair endothelium-dependent relaxation via an EV-mediated transfer of the prooxidant enzyme arginase-1 (Arg1) from RBCs to endothelial cells. These findings reveal events implicated in vascular oxidative stress and set the stage for personalized approaches preventing RBC-EVs’ uptake by the endothelium.

Authors

Sarah Costantino, Shafeeq A. Mohammed, Francesco Paneni

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GLP-1 receptor agonists for the treatment of alcohol use disorder
Gavin N. Petrie, Leah M. Mayo
Gavin N. Petrie, Leah M. Mayo
Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e192414. https://doi.org/10.1172/JCI192414.
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GLP-1 receptor agonists for the treatment of alcohol use disorder

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are widely used in the treatment of metabolic disorders, including type 2 diabetes (T2D) and obesity. These medications primarily function by enhancing insulin secretion; however, emerging evidence suggests that the effects extend beyond metabolic regulation. In this issue of the JCI, Farokhnia et al. evaluated the effects of GLP-1RAs alongside another T2D treatment, dipeptidyl peptidase-4 inhibitors (DPP-4Is), on alcohol consumption in humans and preclinical models. In humans, GLP1-RAs, but not DPP-4Is, were associated with reductions in alcohol consumption. Similarly, DPP-4 inhibition had no effect on alcohol intake in rodents. These findings invite further exploration of the mechanisms by which GLP-1RAs reduce alcohol consumption and redefine our pharmacotherapy approach to alcohol use disorder (AUD) by opening the possibility for application as an early harm-reduction tool.

Authors

Gavin N. Petrie, Leah M. Mayo

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The differential effects of sex hormone therapy on kidney function: insights into biological sex differences
David Collister, Adeera Levin
David Collister, Adeera Levin
Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e191907. https://doi.org/10.1172/JCI191907.
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The differential effects of sex hormone therapy on kidney function: insights into biological sex differences

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Abstract

There are known sex (i.e., biological) and gender (i.e., social) differences in the epidemiology and outcomes of chronic kidney disease. In this issue of the JCI, van Eeghen et al. provide a prospective multicenter observational study of transgender individuals initiating masculinizing and feminizing hormone therapy. Testosterone and estrogen with testosterone blockade had differential effects on kidney physiology including renal plasma blood flow, measured glomerular filtration rate, tubular biomarkers, and various proteins involved in inflammatory and repair pathways. The findings suggest that estrogen is renoprotective and that testosterone may be harmful to kidney function, but requires validation in larger, more diverse cohorts. The insights gained also need to be examined in the context of both endogenous and exogenous sex hormones in individuals over the life cycle.

Authors

David Collister, Adeera Levin

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Developing cell-based therapies for pancreatic ductal adenocarcinoma
Rachel Elizabeth Ann Fincham, … , Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher
Rachel Elizabeth Ann Fincham, … , Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e189513. https://doi.org/10.1172/JCI189513.
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Developing cell-based therapies for pancreatic ductal adenocarcinoma

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Abstract

Prostate stem cell antigen (PSCA) is highly and preferentially expressed on the surface of pancreatic ductal adenocarcinoma (PDAC) cells, raising the promise of tumor-selective cell-based immunotherapies. In this issue of the JCI, Dai et al. harness PSCA for the development of an off-the-shelf chimeric antigen receptor (CAR) invariant natural killer T (iNKT) cell–based treatment for PDAC. Through in vitro experiments and in vivo models, the authors demonstrate selectivity and therapeutic efficacy of PSCA CAR_sIL15 iNKT cells against both gemcitabine-sensitive and -resistant PDAC cells with comparable antitumor activity for freshly produced and frozen off-the-shelf PSCA CAR_sIL15 iNKT cells. This development opens another potential therapeutic option for pancreatic cancer.

Authors

Rachel Elizabeth Ann Fincham, Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher

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Transient pain and long-term gain: adjuvant dose directs immune memory
Pabitra B. Pal, Smita S. Iyer
Pabitra B. Pal, Smita S. Iyer
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e190524. https://doi.org/10.1172/JCI190524.
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Transient pain and long-term gain: adjuvant dose directs immune memory

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Abstract

Vaccine hesitancy is often fueled by fears of side effects; however, most reactions result from innate immune activation and cytokine production, which are required for lasting immunity. For effective vaccines against HIV, innate activation is essential for differentiation of CD4+ T cells into T follicular helper cells (TFH), which guide rare B cells to mature into long-lived plasma cells that produce durable neutralizing antibodies (nAbs). In this issue of the JCI, Parham Ramezani-Rad et al. show that higher doses of saponin QS-21–MPLA nanoparticle (SMNP) adjuvant, combined with BG505 MD39 envelope (Env) protein, enhanced cytokine responses, drove stronger Env-specific TFH responses in blood, and increased Env-specific bone marrow plasma cells compared with lower doses. While tier 2 nAbs were sustained at memory in only a subset of animals, predominantly at the highest adjuvant dose, these findings highlight transient reactogenicity as an essential mechanism — not a flaw — for building durable immune memory.

Authors

Pabitra B. Pal, Smita S. Iyer

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Haptenization as the missing link between vasculitis and myeloperoxidase
Laura Santambrogio
Laura Santambrogio
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e191587. https://doi.org/10.1172/JCI191587.
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Haptenization as the missing link between vasculitis and myeloperoxidase

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Abstract

A wide variety of medications can induce adverse immune events and autoimmune responses such as vasculitis. Mechanistically, small molecule drugs known as haptens bind and modify endogenous proteins, triggering such immune reactions. In this issue of the JCI, Xi and colleagues investigated the immunological mechanism of autoimmune vasculitis associated with hydralazine. Notably, hydralazine-based haptenization modified myeloperoxidase (MPO), inducing the enzyme conformational change. The hydralazine-modified MPO induced IgM antibody specific for the modified enzyme, followed by immune complex precipitation, tissue deposition, and complement activation. These findings provide a mechanism by which hydralazine induces a type III hypersensitivity reaction associated with mild to severe vasculitis. The study serves as an example for understanding haptenation and may inform the development of diagnostics for determining susceptibility to drug-induced allergic or autoimmune responses.

Authors

Laura Santambrogio

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