Issue published September 16, 2025 Previous issue
- Volume 135, Issue 18
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On the cover: Human kidney lymphatics during chronic transplant rejection
Combining 3D imaging and single-cell genomics, Jafree et al. uncover how kidney lymphatics are uniquely organized and how they are rewired in chronic transplant rejection. The cover image shows 3D reconstruction of a confocal image stack from immunolabeled and optically cleared human kidney tissue with chronic transplant rejection. Image credit: Daniyal Jafree and David Long.
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Viewpoints
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Abstract
Authors
Natalie Krahmer, Tobias C. Walther, Robert V. Farese Jr.
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Review Series
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Abstract
Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.
Authors
Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang
×Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD), now the most common cause of chronic liver disease, is estimated to affect around 30% of the global population. In MASLD, chronic liver injury can result in scarring or fibrosis, with the degree of fibrosis being the best-known predictor of adverse clinical outcomes. Hence, there is huge interest in developing new therapies to inhibit or reverse fibrosis in MASLD. However, this has been challenging to achieve, as the biology of fibrosis and candidate antifibrotic therapeutic targets have remained poorly described in patient samples. In recent years, the advent of single-cell and spatial omics approaches that can be applied to human samples have started to transform our understanding of fibrosis biology in MASLD. In this Review, we describe these technological advances and discuss the new insights such studies have provided, focusing on the role of epithelial cell plasticity, mesenchymal cell activation, scar-associated macrophage accumulation, and inflammatory cell stimulation as regulators of liver fibrosis. We also consider how omics techniques can enhance our understanding of evolving concepts in the field, such as hot versus cold fibrosis and the mechanisms of liver fibrosis regression. Finally, we touch on future developments and how they are likely to inform a more mechanistic understanding about how fibrosis might differ between patients and how this could influence optimal therapeutic approaches.
Authors
Fabio Colella, Neil C. Henderson, Prakash Ramachandran
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Review
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Abstract
Rheumatoid arthritis (RA) has a preclinical period of 5–10 years preceding the appearance of joint pain and swelling characteristic of clinical RA. Preclinical RA has been characterized by circulating IgA and IgG classes of autoantibodies targeting citrullinated protein antigens (ACPAs) that are highly specific for future clinical RA, circulating IgA plasmablasts, and autoantibody production at mucosal sites, all of which point toward mucosal tissues as the origin of immune dysregulation. In individuals at risk for developing and with established RA, oral and gut microbial shifts correlate with immune activation. Specific bacterial taxa such as Segatella copri, Subdoligranulum didolesgii, Eggerthella lenta, and Streptococcal species have been shown to contribute to the development and/or perpetuation of RA through mechanisms that include molecular mimicry, antigen citrullination, and disruption of mucosal immunity. Furthermore, microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune homeostasis and offer potential therapeutic avenues. The gut microbiome also influences therapeutic responses by modulating conventional disease-modifying antirheumatic drugs. This Review synthesizes current knowledge on the bacterial microbiome’s role in RA pathogenesis and treatment responses, highlighting microbiome-targeted interventions as potential strategies for disease prevention and management.
Authors
Jing Li, Kristine A. Kuhn
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Commentaries
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Abstract
The hallmark feature of metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic lipid accumulation. A recent search for genes impacting MASLD in mice uncovered the transcriptional repressor T-box 3 (Tbx3) as a top hit. In this issue of the JCI, Mannino et al. investigated the mechanism of action of TBX3 in murine MASLD. Tbx3 deletion protected against MASLD by inducing high density lipoprotein binding protein and stimulating hepatic VLDL secretion. Loss-of-function mutations in human TBX3 identified in MASLD patients displayed a similar protective effect. Collectively, these findings highlight the importance of lipid export in the prevention of MASLD and identify a transcriptional pathway controlling hepatic lipid secretion that is poised for further investigation.
Authors
Jacquelyn J. Maher
×Abstract
Accumulation of the light-reactive heme precursor protoporphyrin IX (PPIX) in blood causes protoporphyria, a disease characterized by severe pain resulting from sunlight exposure, as well as by the occurrence of liver failure in some patients. Thus, decreasing PPIX biosynthesis is a promising strategy to treat protoporphyria. In this issue of the JCI, Ducamp et al. report that inhibition of the glycine plasma membrane transporter GLYT1 using bitopertin decreased PPIX accumulation and ameliorated liver disease using human in vitro and mouse in vivo models. Their findings support the ongoing development of bitopertin to treat protoporphyria, while concurrently pointing to underexplored roles of glycine in erythroid cells.
Authors
Marc Liesa
×Abstract
Cutaneous melanoma (CM) is known for its aggressive behavior, high metastatic potential, and poor prognosis. Mutations in the BRAF gene are common in CM, and patients with BRAF-mutant melanoma often respond well to combined inhibition of BRAF and MEK (BRAFi + MEKi). Although BRAFi + MEKi therapy provides clinical efficacy, the response durability is limited by persistent drug-tolerant residual cells, culminating in relapse. In this issue of the JCI, Tiago et al. confirmed that NR2F1, a dormancy-associated transcription factor, is a key determinant of therapeutic resistance in melanoma. NR2F1 expression was elevated in transcriptomic datasets from patients with minimal residual disease, and in murine and human melanoma models, NR2F1 overexpression reduced therapeutic efficacy and suppressed tumor proliferation and invasion while sustaining mechanistic target of rapamycin complex 1 (mTORC1) transcriptional regulation of relevant genes. Combining BRAFi + MEKi with the mTORC1 inhibitor rapamycin effectively targeted these resistant melanoma cells, suggesting a potential path forward for targeting NR2F1 and mTORC1 signaling in patients with CM.
Authors
Narsimha Mamidi, Swadesh K. Das, Paul B. Fisher
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Research Letter
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Abstract
Authors
Macee C. Owen, Vinay R. Penna, Hao Dun, Wenjun Li, Benjamin J. Kopecky, Kenneth M. Murphy, Daniel Kreisel, Kory J. Lavine
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Research Articles
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Abstract
Lymphatic vessels maintain tissue fluid homeostasis and modulate inflammation, yet their spatial organization and molecular identity in the healthy human kidney, and how these change during chronic transplant rejection, remain poorly defined. Here, we show that lymphatic capillaries initiate adjacent to cortical kidney tubules and lack smooth muscle coverage. These vessels exhibit an organ-specific molecular signature, enriched for CCL14, DNASE1L3, and MDK, with limited expression of canonical immune-trafficking markers found in other organ lymphatics, such as LYVE1 and CXCL8. In allografts with chronic mixed rejection, lymphatics become disorganized and infiltrate the medulla, with their endothelial junctions remodeling from a button-like to a continuous, zipper-like, architecture. Lymphatics in rejecting kidneys localize around and interconnect tertiary lymphoid structures at different maturation stages, with altered intralymphatic and perilymphatic CD4+ T cell distribution. The infiltrating T cells express IFN-γ, which upregulates coinhibitory ligands in lymphatic endothelial cells, including PVR and LGALS9. Simultaneously, lymphatics acquire HLA class II expression and exhibit C4d deposition, consistent with alloantibody binding and complement activation. Together, these findings define the spatial and molecular features of human kidney lymphatics, revealing tolerogenic reprogramming accompanied by structural perturbations during chronic transplant rejection.
Authors
Daniyal J. Jafree, Benjamin J. Stewart, Karen L. Price, Maria Kolatsi-Joannou, Camille Laroche, Barian Mohidin, Benjamin Davis, Hannah Mitchell, Lauren G Russell, Lucía Marinas del Rey, Chun Jing Wang, William J Mason, Byung Il Lee, Lauren Heptinstall, Ayshwarya Subramanian, Gideon Pomeranz, Dale Moulding, Laura Wilson, Tahmina Wickenden, Saif N. Malik, Natalie Holroyd, Claire L. Walsh, Jennifer C. Chandler, Kevin X. Cao, Paul J.D. Winyard, Adrian S. Woolf, Marc Aurel Busche, Simon Walker-Samuel, Lucy S.K. Walker, Tessa Crompton, Peter J. Scambler, Reza Motallebzadeh, Menna R. Clatworthy, David A. Long
×Abstract
While weight loss is highly recommended for those with obesity, >60% regain their lost weight. This weight cycling is associated with an elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss and regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss promoted atherosclerosis resolution independent of plasma cholesterol. Single-cell RNA sequencing and subsequent mechanistic studies indicated that this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fc γ receptor 4 (Fcgr4), helped to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyperinflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.
Authors
Bianca Scolaro, Franziska Krautter, Emily J. Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L. Garabedian, Cyrus A. Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A. Fisher
×Abstract
We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present study shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA’s role in biofilm formation. Collectively, these data reveal a critical mechanism — epigenetic regulation of staphylococcal gene expression — by which phage can regulate virulence to drive adaptive leaps by S. aureus.
Authors
Robert J. Ulrich, Magdalena Podkowik, Rebecca Tierce, Irnov Irnov, Gregory Putzel, Nora M. Samhadaneh, Keenan A. Lacey, Daiane Boff, Sabrina M. Morales, Sohei Makita, Theodora K. Karagounis, Erin E. Zwack, Chunyi Zhou, Randie H. Kim, Karl Drlica, Alejandro Pironti, Harm van Bakel, Victor J. Torres, Bo Shopsin
×Elevated NR2F1 underlies the persistence of invasive disease after treatment of BRAF-mutant melanoma
Abstract
Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient to reduce BRAFi + MEKi effects on tumor growth in vivo, and cell proliferation, death, and invasion in vitro. Effects were linked to genes involved in mTORC1 signaling. These cells were sensitive to the combination of BRAFi, MEKi plus rapamycin. Melanomas from aged mice, known to exhibit decreased responses to BRAFi + MEKi, displayed higher levels of NR2F1 compared to tumors from young mice. Depleting NR2F1 in an aged mouse melanomas improved the response to targeted therapy. These findings show high NR2F1 expression in ‘invasive-state’ residual cells and that targeting NR2F1-high cells with mTORC1 inhibitors may improve outcomes in patients with melanoma.
Authors
Manoela Tiago, Timothy J. Purwin, Casey D. Stefanski, Renaira Oliveira da Silva, Mitchell E. Fane, Yash Chhabra, Jelan I. Haj, Jessica L.F. Teh, Rama Kadamb, Weijia Cai, Sheera R. Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanueva, Inna Chervoneva, Ashani T. Weeraratna, Dan A. Erkes, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin
×Abstract
The role of conventional type 1 DCs (cDC1s) in tolerance induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within allograft and spleen tissue of transplant recipients, and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression in both in vivo cDC1s and in vitro Flt3L-derived cDC1s. Genetic deletion of TGF-β1 in cDC1s prevented induction of antigen-specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced expression of cDC1 TGF-β1, decreased antigen-specific Treg populations, and impaired allograft tolerance. Taken together, our findings implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.
Authors
Samantha L. Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep S. Chandel, Maria-Luisa Alegre, Edward B. Thorp
×Abstract
Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also experience chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small-molecule inhibitor of the erythroid cell-surface glycine transporter GLYT1. We established the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirmed a marked reduction of PPIX in erythroblasts derived from patients with EPP. We demonstrate that bitopertin also reduced erythrocyte and plasma PPIX accumulation in vivo in both EPP and XLPP mouse models. Finally, the reduction in erythroid PPIX ameliorated liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.
Authors
Sarah Ducamp, Min Wu, Juan Putra, Dean R. Campagna, Yi Xiang, Vu Hong, Matthew M. Heeney, Amy K. Dickey, Rebecca K. Leaf, Mark D. Fleming, Brian MacDonald, Paul J. Schmidt
×Abstract
Hypertonic and hyperosmolar stimuli frequently pose challenges to the intestinal tract. Therefore, a resilient epithelial barrier is essential for maintaining gut homeostasis in the presence of osmotic perturbations. Nuclear factor of activated T cells 5 (NFAT5), an osmosensitive transcription factor, primarily maintains cellular homeostasis under hypertonic conditions. However, the osmoprotective role of NFAT5 in enterocyte homeostasis is poorly understood. Here, we demonstrate that NFAT5 was critical for the survival and proliferation of intestinal epithelial cells (IECs) and that its deficiency accelerated chemically induced or spontaneous colitis in mice. Mechanistically, NFAT5 promoted the survival of IECs and the renewal of intestinal stem cells, thereby regulating the production of mucus and antimicrobial compounds, including RegIII and lysozyme, which consequently shape the gut microbial composition to prevent colitis. Transcriptome analysis identified HSP70 as a key downstream target of NFAT5 in epithelial regeneration. Loss- and gain-of-function experiments involving HSP70 revealed that NFAT5 mitigated experimental colitis through IEC Hsp70, which protected stem cells from inflammation-induced injury and maintained barrier function. In conclusion, our study demonstrates what we believe to be a previously unknown role for NFAT5 in dictating the crosstalk between intestinal stem cells and the microbiota, underscoring the importance of the NFAT5/HSP70 axis in maintaining epithelial regeneration related to gut barrier function, balancing microbial composition, and subsequently preventing colitis progression.
Authors
Se-Hyeon Park, Dae Hee Cheon, Yu-Mi Kim, Yeji Choi, Yong-Joon Cho, Bong-Ki Hong, Sang-Hyun Cho, Mi-Na Kweon, Hyug Moo Kwon, Eugene B. Chang, Donghyun Kim, Wan-Uk Kim
×Abstract
Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota–derived histamine as such a factor. We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints. We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist–induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.
Authors
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
×Abstract
Few effective therapeutic options exist after progression on immune checkpoint blockade (ICB) for melanoma. Here, we utilized a platform incorporating transcriptomic profiling, high-throughput drug screening, and murine models to demonstrate the preclinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. High-throughput drug screening targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and after progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg–treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.
Authors
Imran Khan, Aida Rodriguez-Brotons, Anukana Bhattacharjee, Vladimir Bezrookove, Altaf Dar, David De Semir, Mehdi Nosrati, Ryan Ice, Liliana Soroceanu, Stanley P. Leong, Kevin B. Kim, Yihui Shi, James E. Cleaver, James R. Miller III, Pierre-Yves Desprez, John M. Kirkwood, Marcus Bosenberg, Nathan Salomonis, Sean McAllister, Mohammed Kashani-Sabet
×Abstract
Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC), limiting response to immune checkpoint blockade (ICB). While a high–MHC class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the IMpower133 clinical trial, high, but not low, NOTCH1 expression was significantly associated with longer survival with the addition of ICB to chemotherapy among approximately 80% of SCLC patients with NE-enriched tumors (ASCL1-enriched, HR 0.39, P = 0.0012; NEUROD1-enriched, HR 0.44, P = 0.024). Overexpression or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically upregulated MHC class I through epigenetic reactivation of STING. In syngeneic mouse models, Notch1 activation reprogrammed SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression was significantly enriched in high- compared with low-NOTCH1-expressing tumors in IMpower133, validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash antitumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.
Authors
Yoo Sun Kim, Barzin Y. Nabet, Briana N. Cortez, Nai-Yun Sun, Robin Sebastian, Christophe E. Redon, Anagh Ray, Liang Liu, Afeez A. Ishola, Sarah Loew, Anjali Dhall, Sivasish Sindiri, Velimir Gayevskiy, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Noemi Kedei, Thorkell Andresson, Sudipto Das, Suresh Kumar, Alan E. Bers, Hongliang Zhang, Alberto Chiappori, Priyanka Gopal, Mohamed E. Abazeed, Haobin Chen, Mirit I. Aladjem, Yves Pommier, Moises J. Velez, David S. Shames, Nitin Roper
×Abstract
The spliceosome is a critical cellular machinery responsible for pre-mRNA splicing that is essential for the proper expression of genes. Mutations in its core components are increasingly linked to neurodevelopmental disorders, such as primary microcephaly. Here, we investigated the role of SNW domain–containing protein 1 (SNW1), a spliceosomal protein, in splicing integrity and neurodevelopment. We identified 9 heterozygous mutations in the SNW1 gene in patients presenting with primary microcephaly. These mutations impaired SNW1’s interactions with core spliceosomal proteins, leading to defective RNA splicing and reduced protein functionality. Using Drosophila melanogaster and human embryonic stem cell–derived cerebral organoids models, we demonstrated that SNW1 depletion resulted in significant reductions in neural stem cell proliferation and increased apoptosis. RNA-Seq revealed disrupted alternative splicing, especially skipping exons, and altered expression of neurodevelopment-associated genes (CENPE, MEF2C, and NRXN2). Our findings provide crucial insights into the molecular mechanisms by which SNW1 dysfunction contributes to neurodevelopmental disorders and underscore the importance of proper spliceosome function in brain development.
Authors
Lei Ji, Jin Yan, Nicole A. Losurdo, Hua Wang, Liangjie Liu, Keyi Li, Zhen Liu, Zhenming Guo, Jing Xu, Adriana Bibo, Decheng Ren, Ke Yang, Yingying Luo, Fengping Yang, Gui Wang, Zhenglong Xiang, Yuan Wang, Huaizhe Zhan, Hu Pan, Juanli Hu, Jianmin Zhong, Rami Abou Jamra, Pia Zacher, Luciana Musante, Flavio Faletra, Paola Costa, Caterina Zanus, Nathalie Couque, Lyse Ruaud, Anna M. Cueto-González, Hector San Nicolas Fernández, Eduardo Tizzano, Nuria Martinez Gil, Xiaorong Liu, Weiping Liao, Layal Abi Farraj, Alden Y. Huang, Liying Zhang, Aparna Murali, Esther Schmuel, Christina S. Han, Kayla King, Weiyue Gu, Pengchao Wang, Kai Li, Nichole Link, Guang He, Shan Bian, Xiao Mao
×Abstract
Growing evidence links human long noncoding RNAs (lncRNAs) to metabolic disease pathogenesis, yet no FDA-approved drugs target human lncRNAs. Most human lncRNAs lack conservation in other mammals, complicating efforts to define their roles and identify therapeutic targets. Here, we leveraged the concept of functionally conserved lncRNAs (FCLs) — lncRNAs that share function despite no sequence similarity — to develop a framework for identifying human lncRNAs as therapeutic targets for metabolic disorders. We used expression quantitative trait loci mapping and functional conservation analyses to pinpoint human lncRNAs influenced by disease-associated SNPs and with potential functionally conserved mouse equivalents. We identified human and mouse GULLs (glucose and lipid lowering), which regulate glucose and lipid metabolism by binding CRTC2, thereby modulating gluconeogenic genes via CREB and lipogenic genes via SREBP1. Despite their lack of sequence similarity, both lncRNAs demonstrated similar metabolic effects in obese mice, with more pronounced benefits from long-term activation. To identify druggable sites, we mapped GULLs’ binding motifs to CRTC2 (termed GULFs). Standalone human GULF, an RNA oligomer resembling FDA-approved siRNAs, significantly improved glucose and lipid levels in obese mice. This framework highlights functionally conserved human lncRNAs as promising therapeutic targets, exemplified by GULLs’ potential as a glucose- and lipid-lowering therapeutic.
Authors
Zhe Li, Sunmi Seok, Chengfei Jiang, Ping Li, Yonghe Ma, Hang Sun, Haiming Cao
×Abstract
Pathogenic variants in the gene TMPRSS3 are a common cause of hearing loss in humans, although the causal mechanisms remain unknown. Previous work has shown that Tmprss3Y260X/Y260X mice exhibit normal hair cell development, mechanosensory transduction, and spiral ganglion patterning, but experience rapid hair cell death from P12 to P14 at the onset of hearing. Here, we demonstrate that Tmprss3Y260X/Y260X mice display an early and temporary spike in endocochlear potential (EP) prior to the onset of hair cell death. In vitro experiments with cochlear explants from Tmprss3Y260X/Y260X mice and in vivo studies with Tmprss3Y260X/Y260X mice crossed with 2 different mutant models that lacked EP generation promoted hair cell survival. Furthermore, systemic administration of furosemide, a drug that reduces EP in vivo, reduced hair cell death in Tmprss3Y260X/Y260X mice. These findings suggest that extracellular factors, including EP, play a role in TMPRSS3-related hair cell survival and hearing loss, and suggest that modulating EP could be a therapeutic strategy.
Authors
A. Eliot Shearer, Yuan-Siao Chen, Stephanie L. Rouse, Xiaohan Wang, Janmaris Marin Fermin, Kevin T.A. Booth, Jasmine Moawad, Nicole Bianca Libiran, Jinan Li, Hae-Young Kim, Michael Hoa, Rafal Olszewski, Jing-Yu Lei, Ernesto Cabrera, Douglas J. Totten, Bo Zhao, Jeffrey R. Holt, Rick F. Nelson
×Abstract
The germinal center (GC) dark zone (DZ) and light zone represent distinct anatomical regions in lymphoid tissue where B cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse large B cell lymphomas (DLBCLs) with DZ-like gene expression profiles exhibit poor outcomes, though the reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T cells, prompting exploration of whether T cell paucity contributes to DZ-like DLBCL. We used spatial transcriptomic approaches to achieve higher resolution of T cell spatial heterogeneity in the GC and to derive potential pathways that underlie T cell exclusion. We showed that T cell exclusion from the DZ was linked to DNA damage response (DDR) and chromatin compaction molecular features characterizing the spatial DZ signature, and that these programs were independent of activation-induced cytidine deaminase (AID) activity. As ATR is a key regulator of DDR, we tested its role in the T cell inhibitory DZ transcriptional imprint. ATR inhibition reversed not only the DZ transcriptional signature, but also DZ T cell exclusion in DZ-like DLBCL in vitro microfluidic models and in in vivo samples of murine lymphoid tissue. These findings highlight that ATR activity underpins a physiological scenario of immune silencing. ATR inhibition may reverse the immune-silent state and enhance T cell–based immunotherapy in aggressive lymphomas with GC DZ–like characteristics.
Authors
Valeria Cancila, Giorgio Bertolazzi, Allison S.Y. Chan, Giovanni Medico, Giulia Bastianello, Gaia Morello, Daniel Paysan, Clemence Lai, Liang Hong, Girija Shenoy, Patrick W. Jaynes, Giovanna Schiavoni, Fabrizio Mattei, Silvia Piconese, Maria V. Revuelta, Francesco Noto, Luca Businaro, Adele De Ninno, Ilenia Cammarata, Fabio Pagni, Saradha Venkatachalapathy, Sabina Sangaletti, Arianna Di Napoli, Giada Cicio, Davide Vacca, Silvia Lonardi, Luisa Lorenzi, Andrés J.M. Ferreri, Beatrice Belmonte, Min Liu, Manikandan Lakshmanan, Michelle S.N. Ong, Biyan Zhang, Tingyi See, Kong-Peng Lam, Gabriele Varano, Mario P. Colombo, Silvio Bicciato, Giorgio Inghirami, Leandro Cerchietti, Maurilio Ponzoni, Roberta Zappasodi, Evelyn Metzger, Joseph Beechem, Fabio Facchetti, Marco Foiani, Stefano Casola, Anand D. Jeyasekharan, Claudio Tripodo
×Abstract
Gain of plasticity and loss of MHC-II enable tumor cells to evade immune surveillance, contributing to tumor development. Here, we showed that the transcriptional corepressor RCOR2 is a key factor that integrates two epigenetic programs surveilling tumor plasticity and immunogenicity. RCOR2 was upregulated predominantly in tumor cells and promoted tumor development in mice through reducing tumor cell death by CD4+CD8+ T cells and inducing cancer stemness. Mechanistically, RCOR2 repressed RNF43 expression through LSD1-mediated demethylation of histone H3 at lysine 4 to induce activation of Wnt/β-catenin and tumor stemness. Simultaneously, RCOR2 inhibited CIITA expression through HDAC1/2-mediated deacetylation of histone H4 at lysine 16, leading to MHC-II silencing in tumor cells and subsequent impairment of CD4+CD8+ T cell immunosurveillance, thereby promoting immune evasion. RCOR2 loss potentiated anti–PD-1 therapy in mouse models of cancer and correlated with better response to anti–PD-1 therapy in human patients. Collectively, these findings uncover a “two birds with one stone” effect for RCOR2, highlighting its potential as a valuable target for improved cancer therapy.
Authors
Lei Bao, Ming Zhu, Maowu Luo, Ashwani Kumar, Yan Peng, Chao Xing, Yingfei Wang, Weibo Luo
×Abstract
The cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) pathway is intimately associated with antitumoral immunity; however, the direct involvement of this pathway in tumor cell demise remains elusive. Here, we identified a compound, dodecyl 6-hydroxy-2-naphthoate (DHN), that induces pyroptosis in melanoma cells by activating noncanonical cGAS/STING signaling. DHN targets mitochondrial protein cyclophilin D (CypD) to induce the release of mitochondrial DNA, leading to cGAS activation and cyclic GMP-AMP (cGAMP) generation. Meanwhile, DHN-caused intracellular acidification induces protein kinase R-like endoplasmic reticulum kinase (PERK) activation, which promotes STING phosphorylation and polymerization in the presence of cGAMP, thereby facilitating the aggregation of STING in the ER, which serves as a platform to recruit Fas-associated via death domain (FADD) and caspase-8, leading to caspase-8 activation and subsequent gasdermin E cleavage, which ultimately results in pyroptosis of tumor cells and tumor regression in mouse models. The occurrence of this noncanonical cGAS/STING pathway–associated pyroptosis is also observed when both cGAS is activated and intracellular pH declines. Collectively, our findings reveal a pathway that links noncanonical cGAS/STING signaling to gasdermin E–mediated pyroptosis, thereby offering valuable insights for tumor therapy.
Authors
Li Xiao, Yuan-li Ai, Xiang-yu Mi, Han Liang, Xiang Zhi, Liu-zheng Wu, Qi-tao Chen, Tong Gou, Chao Chen, Bo Zhou, Wen-bin Hong, Lu-ming Yao, Jun-jie Chen, Xianming Deng, Fu-nan Li, Qiao Wu, Hang-zi Chen
×Abstract
BACKGROUND Predicting individual vaccine responses is a substantial public health challenge. We developed Immunaut, an open-source, data-driven framework for systems vaccinologists to analyze and predict immunological outcomes across diverse vaccination settings, beyond traditional assessments.METHODS Using a comprehensive live attenuated influenza vaccine (LAIV) dataset from 244 Gambian children, Immunaut integrated prevaccination and postvaccination humoral, mucosal, cellular, and transcriptomic data. Through advanced modeling, our framework provided a holistic, systems-level view of LAIV-induced immunity.RESULTS The analysis identified 3 distinct immunophenotypic profiles driven by baseline immunity: (a) CD8+ T cell responders with strong preexisting immunity boosting memory T cell responses; (b) mucosal responders with prior influenza A virus immunity developing robust mucosal IgA and subsequent influenza B virus seroconversion; and (c) systemic, broad influenza A virus responders starting from immune naivety who mounted broad systemic antibody responses. Pathway analysis revealed how preexisting immune landscapes and baseline features, such as mucosal preparedness and cellular support, quantitatively dictate vaccine outcomes.CONCLUSION Our findings emphasize the power of integrative, predictive frameworks for advancing precision vaccinology. The Immunaut framework is a valuable resource for deciphering vaccine response heterogeneity and can be applied to optimize immunization strategies across diverse populations and vaccine platforms.FUNDING Wellcome Trust (110058/Z/15/Z); Bill & Melinda Gates Foundation (INV-004222); HIC-Vac Consortium; NIAID (R21 AI151917); NIAID CEIRR Network (75N93021C00045).
Authors
Stephanie Hao, Ivan Tomic, Benjamin B. Lindsey, Ya Jankey Jagne, Katja Hoschler, Adam Meijer, Juan Manuel Carreño Quiroz, Philip Meade, Kaori Sano, Chikondi Peno, André G. Costa-Martins, Debby Bogaert, Beate Kampmann, Helder Nakaya, Florian Krammer, Thushan I. de Silva, Adriana Tomic
×Abstract
Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated, MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline-deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.
Authors
Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu
×Abstract
Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhanced IL-10 production. The absence of ICOS reprogrammed ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis and subsequent glucocorticoid receptor (GR) activation. This reprogramming regulated MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.
Authors
Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Mohammad H. Kazemi, Xin Li, Stephen Shen, Omid Akbari
×Abstract
The immune ecosystem is central to maintaining effective defensive responses. However, it remains largely understudied how immune cells in the peripheral blood interact with circulating tumor cells (CTCs) in metastasis. Here, blood analysis of patients with advanced breast cancer revealed that over 75% of CTC-positive blood specimens contained heterotypic CTC clusters with CD45+ white blood cells (WBCs), which correlates with breast cancer subtypes, racial groups, and decreased survival. CTC-WBC clusters included overrepresented T cells and underrepresented neutrophils. Specifically, a rare subset of CD4 and CD8 double-positive T (DPT) cells was 140-fold enriched in CTC clusters versus their frequency in WBCs. DPT cells shared properties with CD4+ and CD8+ T cells but exhibited unique features of T cell exhaustion and immune suppression. Mechanistically, the integrin heterodimer α4β1, also named very late antigen 4 (VLA-4), in DPT cells and its ligand, VCAM1, in tumor cells are essential mediators of DPT-CTC clusters. Neoadjuvant administration of anti-VLA-4 neutralizing antibodies markedly blocked CTC–DPT clusters, inhibited metastasis, and extended mouse survival. These findings highlight a pivotal role of rare DPT cells in fostering cancer dissemination through CTC clustering. It lays a foundation for developing innovative biomarker-guided therapeutic strategies to prevent and target cancer metastasis.
Authors
David Scholten, Lamiaa El-Shennawy, Yuzhi Jia, Youbin Zhang, Elizabeth Hyun, Carolina Reduzzi, Andrew D. Hoffmann, Hannah F. Almubarak, Fangjia Tong, Nurmaa K. Dashzeveg, Yuanfei Sun, Joshua R. Squires, Janice Lu, Leonidas C. Platanias, Clive H. Wasserfall, William J. Gradishar, Massimo Cristofanilli, Deyu Fang, Huiping Liu
×Abstract
Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delayed tumor growth and synergized with anti–PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.
Authors
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
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Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by complex interactions between lipotoxicity, ER stress responses, and immune-mediated inflammation. We identified enrichment of the proinflammatory alarmin S100 calcium-binding protein A11 (S100A11) on extracellular vesicles stimulated by palmitate-induced lipotoxic ER stress with concomitant upregulation of hepatocellular S100A11 abundance in an IRE1A-XBP1s dependent manner. We next investigated the epigenetic mechanisms that regulate this stress response. Publicly available human liver ChIP-Seq GEO datasets demonstrated a region of histone H3 lysine 27 (H3K27) acetylation upstream to the S100A11 promoter. H3K27acetylation ChIP-qPCR demonstrated a positive correlation between lipotoxic ER stress and H3K27acetylation of the region, which we termed Lipotoxicity Influenced Enhancer (LIE) domain. CRISPR-mediated repression of the LIE domain reduced palmitate-induced H3K27acetylation and corresponding S100A11 upregulation in Huh7 cells and immortalized mouse hepatocytes. Silencing of the murine LIE in two independent steatohepatitis models demonstrated reduced S100a11 upregulation and attenuated liver injury. We confirmed H3K27acetylation and XBP1s occupancy at the LIE domain in human MASH liver samples and an increase in hepatocyte-derived S100A11-enriched extracellular vesicles in MASH patient plasma. Our studies demonstrate a LIE domain which mediates hepatic S100A11 upregulation. This pathway may be a potential therapeutic target in MASH.
Authors
P. Vineeth Daniel, Hanna L. Erickson, Daheui Choi, Feda H. Hamdan, Yasuhiko Nakao, Gyanendra Puri, Takahito Nishihara, Yeriel Yoon, Amy S. Mauer, Debanjali Dasgupta, Jill Thompson, Alexander Revzin, Harmeet Malhi
Abstract
Authors
Bowen Yan, Qingchen Yuan, Marco M. Buttigieg, Prabhjot Kaur, Annalisse R. McKee, Daniil E. Shabashvili, Caitlyn Vlasschaert, Alexander G. Bick, Michael J. Rauh, Olga A. Guryanova
Abstract
Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, contributes to age-related cardiovascular diseases (CVD) and other aging-related pathologies. Humans with a heterozygous loss-of-function SERPINE1 variant exhibit protection against aging and cardiometabolic dysfunction. We engineered a mouse model mimicking the human mutation (Serpine1TA700/+) and compared cardiovascular responses with wild-type littermates. Serpine1TA700/+ mice lived 20% longer than littermate controls. Under L-NG-Nitro-arginine methyl ester (L-NAME)-induced vascular stress, Serpine1TA700/+ mice exhibited diminished pulse wave velocity (PWV), lower systolic hypertension (SBP), and preserved left ventricular diastolic function compared to controls. Conversely, PAI-1-overexpressing mice exhibited measurements indicating accelerated cardiovascular aging. Single cell transcriptomics of Serpine1TA700/+ aortas revealed a vascular-protective mechanism with downregulation of extracellular matrix regulators Ccn1 and Itgb1. Serpine1TA700/+ aortas were also enriched in a cluster of smooth muscle cells that exhibited plasticity. Finally, PAI-1 pharmacological inhibition normalized SBP and reversed L-NAME-induced PWV elevation. These findings demonstrate that PAI-1 reduction protects against cardiovascular aging-related phenotypes, while PAI-1 excess promotes vascular pathological changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related CVD.
Authors
Alireza Khoddam, Anthony Kalousdian, Mesut Eren, Saul Soberanes, Andrew Decker, Elizabeth J. Lux, Benjamin W. Zywicki, Brian Dinh, Bedirhan Boztepe, Baljash S. Cheema, Carla M. Cuda, Hiam Abdala-Valencia, Arun Sivakumar, Toshio Miyata, Lisa D. Wilsbacher, Douglas E. Vaughan
Abstract
Teplizumab, a humanized anti-CD3 monoclonal antibody, represents a breakthrough in autoimmune type 1 diabetes (T1D) treatment, by delaying clinical onset in stage 2 and slowing progression in early stage 3. However, therapeutic responses are heterogeneous. To better understand this variability, we applied single-cell transcriptomics to paired peripheral blood and pancreas samples from anti-mouse CD3-treated non-obese diabetic (NOD) mice and identified distinct gene signatures associated with therapy outcome, with consistent patterns across compartments. Success-associated signatures were enriched in NK/CD8⁺ T cells and other immune cell types, whereas resistance signatures were predominantly expressed by neutrophils. The immune communities underlying these response signatures were confirmed in human whole-blood sequencing data from the AbATE study at 6 months, which assessed teplizumab therapy in stage 3 T1D. Furthermore, baseline expression profiling in the human TN10 (stage 2) and AbATE (stage 3) cohorts identified immune signatures predictive of therapy response, T cell-enriched signatures in responders and neutrophil-enriched signatures in non-responders, highlighting the roles of both adaptive and innate immunity in determining teplizumab outcome. Using an elastic-net logistic regression model, we developed a 26-gene blood-based signature predicting teplizumab response (AUC = 0.97). These findings demonstrate the predictive potential of immune gene signatures and the value of transcriptomic profiling in guiding individualized treatment strategies with teplizumab in T1D.
Authors
Gabriele Sassi, Pierre Lemaitre, Laia Fernández Calvo, Francesca Lodi, Álvaro Cortés Calabuig, Samal Bissenova, Amber Wouters, Laure Degroote, Marijke Viaene, Niels Vandamme, Lauren Higdon, Peter S. Linsley, S. Alice Long, Chantal Mathieu, Conny Gysemans
Abstract
Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg “effector” differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an “effector” phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.
Authors
Cameron McDonald-Hyman, Ethan G. Aguilar, Ewoud B. Compeer, Michael C. Zaiken, Stephanie Y. Rhee, Fathima A. Mohamed, Jemma H. Larson, Michael L. Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L. Sleeth, Kyle D. Smith, Jennifer S. Whangbo, Jerome Ritz, Tim D. Sparwasser, Roddy S. O'Connor, Peter A. Crawford, Jeffrey C. Rathmell, Leslie S. Kean, Robert Zeiser, Keli L. Hippen, Michael L. Dustin, Bruce R. Blazar
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Series edited by Ben Z. Stanger
Pancreatic Cancer
Series edited by Ben Z. Stanger
Pancreatic ductal adenocarcinoma (PDAC) has among the poorest prognosis and highest refractory rates of all tumor types. The reviews in this series, by Dr. Ben Z. Stanger, bring together experts across multiple disciplines to explore what makes PDAC and other pancreatic cancers so distinctively challenging and provide an update on recent multipronged approaches aimed at improving early diagnosis and treatment.
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