Date unavailable
James R. Rose, Yusho Ishii, Arezou Khosroshahi, Sakeenah Hicks, Scott A. Jenks, Christopher D. Scharer, Ignacio Sanz, Jeremy M. Boss
Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with alternating phases of heightened symptoms and periods of disease inactivity. Our investigation focuses on the distinct molecular profiles of resting naive B cells from both active and inactive SLE states in female adults, primarily of Black ancestry. We identified a distinct transcriptome and epigenome during inactive SLE. Transcriptional patterns indicated an increase in distinct cytokine signaling pathway expression in SLE B cells, encompassing both common and disease activity–specific components. Specifically, while both disease states exhibited interferon signatures, increased expression of IL-12, TNF-α/NF-κB, and CD40 signaling pathway genes was enriched in inactive disease. While some regions exhibited comparable epigenetic features in both disease states, such as TLR7 signaling genes, others were distinct. Chromatin accessibility in inactive disease indicated the involvement of MEF2 and bHLH family factors, such as E2A/E2-2, while active disease regions were defined by IRF family factors. This study illuminates both disease-associated programs and molecular changes to cell activation pathways capable of directing B cells toward diverse effector fates in active or inactive SLE. Our data also offer insights of particular importance for the design and monitoring of B cell–targeting treatments.
Date unavailable
Kristen S. Young, Sean W. Fanning
One in eight women will be diagnosed with breast cancer in their lifetime. Most breast cancers express estrogen receptor α (ERα) and depend on its signaling, which promotes tumor growth, survival, and metastatic spread through hormone-dependent transcriptional reprogramming. Selective estrogen receptor degraders/downregulators (SERDs), such as fulvestrant (faslodex), which was FDA approved in 2002, are second-line endocrine therapies for the treatment of advanced metastatic disease. Tumors containing activating hotspot mutations in ESR1 (the gene encoding ERα) retain some sensitivity to fulvestrant but require higher doses to achieve inhibition of the mutant receptor. Substantial efforts to develop next-generation SERDs with improved pharmacology over fulvestrant have led to the FDA approval of the first-in-class orally available SERD elacestrant (Orserdu), followed by imlunestrant (Inluriyo), and the anticipated approval of several more therapies. Excitingly, recent studies show that in addition to their previously described antitumoral mechanisms, SERDs also act by increasing antitumor immunity. In this Review, we detail the current SERD clinical landscape and our emerging understanding of the interplay among SERDs, breast cancer cells, and the tumor immune microenvironment.
Date unavailable
Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler, Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler
Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, NaV1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.
Date unavailable
Sarah K. Royse, Rajesh Narendran, Sarah K. Royse, Rajesh Narendran
Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to target synaptic loss will require human studies that clarify their clinical relevance of these changes. In the current issue, Zakiniaeiz et al. demonstrate that AUD and alcohol consumption are associated with lower synaptic vesicle glycoprotein 2a (SV2A) expression, indexed by regional [11C]UCB-J PET. This is, to our knowledge, the first in vivo evidence of relationships between synaptic density and alcohol use, and, as such, it represents an important step toward understanding how AUD influences brain structure and function. Here, we describe two longstanding clinical issues in the AUD population — relapse and dementia risk — and how the results of the present study may guide future investigations of these issues.
Date unavailable
Laura L. Hernandez
Lactation insufficiency in postpartum women has been associated with obesity and insulin resistance, among other risk factors. Challenges related to translating findings from animal models of lactation and the limited ability to study pregnant and lactating women in clinical trials have impeded more detailed mechanistic understanding of this relationship. In this issue of the JCI, Meng et al. combined studies in human milk samples and in vitro mammary epithelial cell models from humans and rodents to provide compelling evidence that mitochondrial dysfunction mediates the link between insulin resistance and lactation insufficiency. Notably, they observed that chronic exposure to high levels of insulin led to mitochondrial fragmentation and loss of volume in mouse mammary epithelial cells. This framework linking mitochondria, insulin signaling, and lactation should be extended to in vivo models and primary human tissues to better define the mechanisms supporting successful lactation.
Date unavailable
Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad, Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad
BACKGROUND Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS.METHODS We performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 64).RESULTS After VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data.CONCLUSION MBS/VSG prompts kidney molecular adaptations, providing potential targets for nonsurgical interventions against obesity- and diabetes-associated kidney disease.FUNDING University of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.
Date unavailable
Pablo Penaloza-MacMaster
Date unavailable
Saniya Kari, Aymeline Debonlier, Thibault Angles, Beatriz Chaves, Charles Grosjean, Florence Bucciarelli, Valérie Duplan-Eche, Lucie Nozeran, Jessica Lavery, Elena Morandi, Beatrice Pignolet, Max Mimpen, Joost Smolders, Roland Liblau, Abdelhadi Saoudi, Jan Damoiseaux, Frederick Masson, Loïc Dupré, Anne L. Astier
Multiple sclerosis (MS) is a complex inflammatory disease of the CNS resulting from an intricate interplay between genetic predisposition and environmental factors. Vitamin D (VD) deficiency is one of the established risk factors for MS. CD46 costimulation of CD4+ T cells induces a switch from Th1 to type I regulatory cells (Tr1), characterized by increased IL-10 production. This switch is impaired in MS T cells but can be restored by VD, which also strongly promotes expression of CD226 on CD46-activated T cells. The rs763361 polymorphism in the CD226 gene, resulting in a nonsynonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that expression of this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFN-γ/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which promotes the Tr1 phenotype. LFA-1–mediated Tr1 differentiation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. Our study unveils how, in the context of MS susceptibility, a genetic polymorphism and an environmental factor act in concert to control the differentiation of Tr1 cells.
Date unavailable
Aarti Asnani
Efferocytosis, or the clearance of apoptotic cells by macrophages, has been implicated in tissue resolution that promotes disease regression in atherosclerosis and other diseases of chronic inflammation. The mechanisms by which efferocytosis leads to pro-resolving macrophage reprogramming have not been fully defined. In this issue of the JCI, Avrampou and colleagues found that efferocytosis activates DNA-methyltransferase-3A (DNMT3A) to promote base excision repair and suppress oxidized DNA. Moreover, they provide evidence that DNMT3A enabled tissue repair in the context of plaque regression in a mouse model of atherosclerosis. Human studies have linked DNMT3A mutation–mediated clonal hematopoiesis (DNMT3A-CH) with atherosclerosis. The findings of Avrampou et al. linking DNMT3A function to efferocytosis-mediated tissue repair suggest that this pathway could be modulated therapeutically to minimize cardiovascular events in patients.
Date unavailable
Declan F. McCole, Declan F. McCole
Crohn’s disease can occur anywhere along the small and/or large intestines, but most commonly occurs in the terminal ileum or ascending colon. Factors governing this region-specific inflammation are poorly understood. In this issue of the JCI, Spencer et al. used a TNF-driven mouse model of small intestinal Crohn’s disease to identify a specific bacterial pathobiont, Chlamydia muridarum, as a necessary and sufficient driver of region-restricted inflammation. C. muridarum triggered increased goblet cell expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the mouse proximal colon, analogous to the human ascending colon. IDO1 metabolism of tryptophan stimulated increased levels of kyneurine, and suppression of this IDO1/kyneurine axis alleviated C. muridarum–provoked inflammation in the proximal colon but not the terminal ileum. Analysis of scRNA-seq datasets from patients with Crohn’s disease with ascending colon involvement also supported increased IDO1 expression in a subpopulation of crypt surface epithelial cells. The study highlights a process by which bacterial pathobionts promote region-specific intestinal inflammation.
Date unavailable
Quan-Son Eric Le, Luis E. Rosas-Vidal
Trauma-related neuropsychiatric disorders are commonly treated with exposure-based therapy, an approach based on fear extinction, in which fear memory and expression are suppressed by repeated exposure to the inciting fear stimulus. Fear extinction–focused research often investigates mechanisms of fear inhibition, but positive affect may also contribute to facilitating extinction. In this issue of the JCI, Lin et al. used activity-dependent neuronal labeling in a model of fear extinction to tag extinction-activated medial prefrontal cortex (mPFC) ensembles, identifying functionally distinct projections to the zona incerta (ZI) and supramamillary nucleus (SuM). While mPFC-ZI projections governed extinction retrieval, mPFC-SuM projections encoded positive affect and reinforced fear extinction persistence. Additionally, Lin et al. discovered that SIRT1-expressing mPFC-SuM extinction-recruited projections control extinction relapse vulnerability, showing that SIRT1 overexpression can be leveraged to reduce fear relapse. Overall, this study shows that key cortico-hypothalamic projections manage extinction retrieval and positive affect to promote fear extinction.
Date unavailable
Aditya Ganju, Shyam Rao, Mark A. Dickson, Robert A. Lefkowitz, Chris Thompson, Jin Cheng, Katia Manova, Adriana Haimovitz-Friedman, Gary Schwartz, Zhigang Zhang, Zvi Fuks, William D. Tap, Richard Kolesnick
Transport of nucleoside chemotherapeutic drugs into tumor cells is primarily accomplished through equilibrative nucleoside transporter 1 (ENT1), which is considered constitutively active. Drugs are redistributed via ENT1 across lipid bilayers via facilitated diffusion. Here we discover that ENT1 is not constitutively active, but rather requires activation of acid sphingomyelinase (ASMase) by gemcitabine, generating ceramide-rich platforms (CRPs) on external plasma membranes of endothelial and tumor cells into which ENT1 inserts, dimerizing therein to functionalize transmembrane gemcitabine transport. Whereas sarcoma cells synthesize minimal ASMase, they take up gemcitabine poorly in vitro and in murine xenografts. A strategy designed to augment gemcitabine-induced ASMase secretion into the extravascular space by ASMase-rich neo-angiogenic cells, which then targets tumor cell plasma membranes, yields “bystander” CRPs on sarcoma cells and ENT1 insertion therein, conferring markedly enhanced gemcitabine uptake and xenograft response. Engaging this biology in a prospective phase II clinical trial in advanced sarcoma yielded robust volumetric changes in evaluated tumors that developed early and were often durable.
Date unavailable
Jianan Lu, Qia Zhang, Jiarui Chen, Huaming Li, An Ping, Ziyang Jin, Xiaotao Zhang, Yichen Gu, Xuejiao Dai, Zihong Chen, Yajun Qian, Guoqiang Zhang, Jun Yu, Jianmin Zhang, Ligen Shi
The neutrophil-to-lymphocyte ratio (NLR) is associated with unfavorable prognosis and hemorrhagic transformation (HT) in patients with ischemic stroke, yet the underlying mechanisms remain unclear. Using patient samples and a murine stroke model, we identified CD8+ regulatory T cells (CD8 Tregs) as key regulators of neutrophil homeostasis after ischemic stroke, thereby limiting endothelial disruption and HT. Loss of CD8 Tregs expanded circulating neutrophils by extending their lifespan rather than altering proliferation, bone marrow release, or direct cytotoxicity. Mechanistically, CD8 Tregs shortened neutrophil lifespan by modulating HIF-1α–dependent glycolytic activity and relieving PD-L1–mediated suppression of bone marrow clearance. Finally, coculture experiments with human CD8 Tregs and neutrophils revealed similar neutrophil-regulatory effects, accompanied by improved endothelial barrier integrity. These findings reveal a previously unrecognized CD8 Treg–neutrophil axis and suggest potential therapeutic strategies for preventing HT after stroke.
Date unavailable
Mengting Xu, Xuwen Lin, Hanchi Xu, Hongmei Hu, Xinying Xue, Qing Zhang, Dianping Yu, Saisai Tian, Mei Xie, Linyang Li, Xiaoyu Tao, Xinru Li, Simeng Li, Shize Xie, Yating Tian, Xia Liu, Hanchen Xu, Qun Wang, Weidong Zhang, Sanhong Liu
Date unavailable
Shijie Wang, Lisa Elia, Weiyi Liu, Steven Finkbeiner
Most neurodegenerative diseases reflect patient-specific combinations of polygenic risk variants interacting with aging and environmental factors, rather than a single causative mutation. Phase III clinical trial failure rates for neurodegenerative indications exceed 95%, reflecting in part the limitations of existing preclinical systems to fully model the human genetic context of disease. Patient-derived induced pluripotent stem cells (iPSCs) have the potential to address this shortcoming by faithfully recapitulating human cell biology and preserving each patient’s complete genetic architecture. This Review examines iPSC-based models of neurodegeneration across three themes. First, we discuss mechanisms revealed by these models, from convergent pathways uncovered by familial mutations to early evidence that sporadic disease biology is accessible at sufficient cohort scale. Second, we evaluate culture systems from 2-dimensional monocultures to organoids, examining how increasing complexity expands addressable biological questions while introducing trade-offs. Third, we address the aging problem: reprogramming erases epigenetic signatures of donor aging, removing the cellular context in which late-onset sporadic neurodegeneration emerges. We discuss strategies approximating aging in iPSC-derived neurons and highlight direct conversion strategies that preserve native epigenetic age, enabling access to age-dependent phenotypes. We propose a framework matching model systems to biological questions, improving mechanistic understanding and therapeutic development.
Date unavailable
Yixiang Li, Yasmin N. Laimon, Hyeonseo Cho, Marina Vivero, Gabriel Roberti De Oliveira, Maxwell D. Seager, Andrew Delcea, Varunika Savla, Yuting Chen, Yavuz T. Durmaz, Xintao Qiu, Shweta Kukreja, Rong Li, Talal El Zarif, Wesley Lu, McKayla Van Orden, Jacob E. Berchuck, Roderick T. Bronson, Shuqiang Li, Hongbin Ji, David A. Barbie, Katerina Politi, Matthew L. Freedman, Henry W. Long, Sabina Signoretti, Matthew G. Oser
Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small-cell lung cancer (SCLC). Although usually distinct, rare combined LUAD/SCLC tumors occur, and LUAD can transform into SCLC as a mechanism of resistance to targeted therapies, particularly in EGFR-mutant LUAD tumors with RB1/TP53 inactivation. Although PRC2 complex expression increases during this transformation, its functional role remains unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we found that inactivation of EED, the core PRC2 scaffolding subunit, impaired SCLC tumorigenesis and promoted LUAD histological identity, likely through a NEUROD1-positive intermediate state. Mechanistically, EED loss derepressed bivalent genes comarked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes and NEUROD1. These same LUAD oncogenic signaling genes were bivalently repressed in human SCLC patient-derived xenografts, suggesting a conserved PRC2-dependent mechanism that represses LUAD oncogenic signaling and thereby supports the SCLC neuroendocrine identity. In a complementary EGFR-mutant LUAD GEMM with Rb1 and Trp53 inactivation, EED inactivation at tumor initiation prevented the emergence of SCLC histology after EGFR oncogene withdrawal and redirected recurrent tumors toward mucinous LUAD states with reduced spontaneous metastasis. These findings identify PRC2/EED as a regulator of SCLC neuroendocrine identity and nominate pharmacologic EED inhibition for future investigation in therapy-associated LUAD-to-SCLC transformation.
Date unavailable
Emily Feng, Alexa Mansour, Elizabeth Balint, Alyssa Mark, Sofia Tramonte, Jonathan K. Monteiro, Madison Read, Marie Joe Adaimy, Zhou Xing, Matthias Mack, Sergei V. Kotenko, Deanna M. Santer, Ali A. Ashkar
Interferon lambda (IFN-λ) has emerged as a critical inducer of immune regulation in addition to its mucosal antiviral properties. However, the cellular and molecular mechanisms that govern its dual role during viral infections remain unclear. Here, we discovered that mucosal delivery of IFN-λ abrogates the herpes simplex virus type 2–induced (HSV-2-induced) vaginal tissue pathology observed in the absence of type I IFN signaling, through drastically inhibiting IL-6 production. At the same time, we demonstrated that IFN-λ rescued local production of CD4+ T cell–dependent IFN-γ, which is essential for protection against the development of toxic megacolon following genital HSV-2 infection. Mechanistically, we found that IFN-λ enhances the differentiation of CCR2+Ly6Chi cells into monocyte-derived antigen-presenting cells, thereby boosting T cell responses. In vivo depletion of CCR2+ cells abrogated this phenomenon. Together, these findings suggest that IFN-λ orchestrates a potent antiviral response, inhibiting hyperinflammatory responses while selectively augmenting effector T cell function. This study positions IFN-λ as a promising therapeutic candidate for enhancing local antiviral immunity and offers new insights into the regulation of immune responses in the context of mucosal viral infections.
Date unavailable
Diana B. Voss, Emily J. Shields, Andrey Poleshko, Li Li, Jun Li, Lizhou Wang, Mariacristina Calcagno, Rajan Jain, Cheryl L. Smith, Jonathan A. Epstein.
Date unavailable
Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka, Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka
Mild traumatic brain injury (mTBI) from a closed-head injury (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI (mCHI) is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA-seq analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation, and astrocyte reactivity persisted up to 21 days in a model for mTBI, with significant reduction of this pattern in Asc–/– mice. Importantly, mild cognitive impairment induced after mCHI was largely abrogated in Asc–/– mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mCHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
Date unavailable
Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima, Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima
Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and patients with obesity often develop cardiac hypertrophy and diastolic dysfunction, termed obesity cardiomyopathy. Proinflammatory cytokines, including IL-6, have been implicated in the pathogenesis of the cardiac dysfunction associated with obesity cardiomyopathy. Elevation of FFAs induced by high-fat diet (HFD) consumption induced diastolic dysfunction in the heart as early as after 1 month. HFD consumption directly stimulated IL-6 production in cardiomyocytes before local inflammation developed and induced diastolic dysfunction even in the presence of macrophage depletion with clodronate in the heart. PPARα played an essential role in mediating Il6 transcription in response to HFD consumption by forming a heterodimer with p50/RelA and binding to the NF-κB element in cardiomyocytes. Local production of IL-6 in cardiomyocytes, in turn, mediated the development of diastolic cardiac dysfunction. HFD-induced diastolic dysfunction was attenuated by cardiac-specific deletion of either Pparα or Il6, as well as by interference with the PPARα–NF-κB heterodimer formation by a molecular decoy. These results suggest elevated FFA levels directly upregulate Il6 through the PPARα–NF-κB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.
Date unavailable
Hao Zhou, Tiantian Lu, Zhuoqun Gao, Can Cui, Zhiqiang Fang, Yu You, Jing Jiang, Jinjin Xu, Fang Wei, Jing Yu, Hu Zhou, Jinsong Li, Jian Luo, Lei Zhang, Yunyun Jin
Osteoarthritis (OA) is the most common degenerative joint disease. However, the molecular mechanisms underlying OA-induced cartilage degeneration remain elusive. Here, we identify IFN regulatory factor 2 binding protein 2 (IRF2BP2) as an important regulator of chondrocyte differentiation and articular cartilage regeneration. Irf2bp2 deficiency promoted chondrogenesis and inhibited chondrocyte terminal differentiation by transcriptionally upregulating the key chondrogenic marker SRY-box transcription factor 9 (SOX9), inducing its ectopic expression in the hypertrophic zone. Cartilage-specific KO of Irf2bp2 elevated SOX9 levels, attenuated OA progression in the destabilization of the medial meniscus (DMM) model, and enhanced cartilage regeneration and hyalinization in the microfracture model. Mechanistically, IRF2BP2 bound to and stabilized Fos-related antigen 2 (FOSL2), an activator protein 1 (AP-1) family member, thereby facilitating FOSL2/c-Jun complex formation and repressing SOX9 expression. Adeno-associated virus–mediated (AAV-mediated) FOSL2 overexpression reversed the protective phenotype observed in Irf2bp2-deficient mice. These findings establish the Hippo/IRF2BP2/FOSL2/SOX9 regulatory axis as critical for cartilage regeneration. Importantly, AAV-mediated IRF2BP2 knockdown, pharmacological targeting of the IRF2BP2/AP-1 axis using T-5224, and delivery of a peptide that disrupts IRF2BP2-FOSL2 binding via intra-articular injection all preserved cartilage integrity, offering potential therapeutic strategies for OA and cartilage regeneration.
Date unavailable
Ze-Jie Lin, Xin-Rong Wu, Ming-Yang Wei, Zheng-Kai Lao, Xiang Lan, Yan-Jiao Wu, Wei-Guang Li, Tian-Le Xu, Li-Na Huang, Xue Gu
Effective psychotherapeutic interventions for posttraumatic stress disorder (PTSD) rely on fear extinction to suppress maladaptive fear responses, yet their long-term efficacy is limited by high relapse rates. Notably, extinction involves not only fear inhibition but also affective engagement. However, whether and how internal affective components contribute to extinction retrieval and long-term persistence remain unclear. Here, we demonstrate that positive affective experiences arising during extinction govern the long-term persistence of extinction and resistance to spontaneous recovery. We identify a subpopulation of medial prefrontal cortex (mPFC) extinction neurons projecting to supramammillary nucleus glutamatergic (SuMGlu) neurons that encode positive affective experience during extinction and selectively govern long-term extinction persistence. This ensemble is spatially, anatomically, and transcriptionally distinct from mPFC extinction neurons projecting to zona incerta somatostatin-expressing (ZISST) neurons, which primarily support extinction retrieval. Transcriptomic profiling reveals enrichment of sirtuin 1 (Sirt1) within SuM-projecting extinction ensembles, and bidirectional manipulation of SIRT1 alters extinction relapse vulnerability in a PTSD mouse model. These findings provide a cortical-hypothalamic framework incorporating molecular features that governs the long-term persistence of fear extinction and resistance to relapse through positive affective processes.
Date unavailable
Song Qin, Ninan Dai, Fengyun Xu, Cindy Zhuang, Judith Hellman
Sepsis is a systemic vascular disorder in which endothelial activation, dysfunction, and structural injury contribute to shock, microcirculatory failure, immunothrombosis, and multiorgan dysfunction. Sepsis-associated endotheliopathy is not a uniform process but a dynamic trajectory that evolves from adaptive endothelial activation toward functional disruption, structural injury, and organ-specific vascular failure. In this Review, we propose a phenotype- and trajectory-oriented framework that integrates clinical manifestations, molecular mechanisms, and translational assessment of endothelial dysfunction in sepsis. We focus on four major clinically recognizable modes of endothelial dysfunction that often overlap and evolve over the course of sepsis. We further discuss biology-anchored biomarker panels, bedside physiological surrogates, and serial trajectory-based assessment as complementary approaches for identifying endothelial states, refining risk stratification, and guiding future precision strategies. Finally, we describe implications for biomarker-enriched clinical trials, microvascular-informed resuscitation, and endotype-guided endothelial cell–targeted therapies. Viewing sepsis through the lens of dynamic endotheliopathy provides a framework linking vascular biology to clinically interpretable trajectories and may facilitate the development of personalized approaches to endothelial cell–directed care.
Date unavailable
Diwakar Turaga, Chang-Ru Tsai, Yuka Morikawa, Hanna J. Tadros, Yi Zhao, Lalita Wadhwa, Iki Adachi, Xiao Li, James F. Martin
Date unavailable
Satoshi Konishi, Khaliun Enkhbayar, Shuyu Liu, Naoya Miyashita, Yoshihiko Kobayashi, Vera Hutchison, Ashna Sai, Pankaj Agarwal, Jonathan Witonsky, Nathan D. Jackson, Max A. Seibold, Jichao Chen, Aleksandra Tata, Purushothama Rao Tata, Satoshi Konishi, Khaliun Enkhbayar, Shuyu Liu, Naoya Miyashita, Yoshihiko Kobayashi, Vera Hutchison, Ashna Sai, Pankaj Agarwal, Jonathan Witonsky, Nathan D. Jackson, Max A. Seibold, Jichao Chen, Aleksandra Tata, Purushothama Rao Tata
Cells exhibit diverse sizes and shapes, tailored for functional needs of tissues. Lung alveoli are lined by large, extremely thin epithelial alveolar type 1 cells (AT1s). Their characteristic morphology is essential for lung function and must be restored after injury. The mechanisms underlying small, cuboidal alveolar type 2 cell (AT2) differentiation into thin AT1s remain elusive. Here, we demonstrated that AT2s undergo a stepwise morphological transformation characterized by the development of a unique thick microtubule (MT) bundle organization, critical for AT1 morphology. Using AT2 cultures and in vivo genetic loss-of-function models, we found that MT bundling occurred in a transitional cell state during AT2 differentiation and was regulated by the TP53/TAU (encoded by the microtubule-associated protein tau [MAPT] gene) signaling axis. Notably, TAU underwent a linear clustering process, forming beads-on-a-string-like pattern that preceded thick MT bundle formation. Genetic gain or loss of function of TAU in mouse or human models prevented the formation of thick MT bundles, highlighting the critical role of precise TAU levels in generating ultrathin AT1s. This defect was associated with increased tissue fibrosis following bleomycin-induced injury in vivo. GWAS analysis revealed risk variants in the MAPT locus in lung diseases. Moreover, TP53 controlled TAU expression and its loss phenocopied TAU deficiency. This work revealed an unexpected role for TAU in organizing MT bundles during AT2 differentiation.
Date unavailable
Phan Q. Duy, Benjamin C. Reeves, Huanxing Sun, Xueyan Peng, Pazhanichamy Kalailingam, Garrett Allington, Evan Dennis, Le Thi Hao, Lei Wang, David Rufino-Ramos, Shujuan Zhao, Qiang Li, Neel H. Mehta, William C. Davalan, Mason Blacker, Anthony J. Piscopo, Shozeb Haider, Baojian Fan, Kedous Y. Mekbib, Shuai Shao, Carol Nelson-Williams, Tukiet T. Lam, Benjamin P. Kleinstiver, Patricia L. Musolino, Seth L. Alper, Sheng Chih Jin, Erica L. Herzog, Kristopher T. Kahle
Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged ventricles filled with cerebrospinal fluid (CSF), is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein growth factor receptor-bound protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly coexpressed with 1 of its known upstream RTK partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. IP validated GRB2-CSF1R binding in mouse microglial cells and a human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (nonobstructive) hydrocephalus, mimicking the condition of patients with the GRB2 mutation. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.
Date unavailable
Daria Seriak, Jun Yong Kim, Geoffrey I. Shapiro, Antonio Giordano
Cell-cycle dysregulation is a central driver of breast cancer progression and a major therapeutic vulnerability, particularly in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) disease. The clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy has transformed treatment paradigms and established cell-cycle targeting as a cornerstone of care. However, important challenges remain, including hematologic toxicity, incomplete and largely cytostatic responses, and the near-universal development of resistance. These limitations have highlighted the need for next-generation CDK-directed strategies capable of improving selectivity, extending disease control, and overcoming adaptive escape pathways. This Review examines the evolving landscape of CDK-targeted therapeutics in breast cancer, with particular emphasis on emerging CDK4-selective inhibitors, CDK2-directed approaches, and broader multi-CDK strategies. We discuss the biological rationale underpinning these agents, the mechanisms of resistance that have informed their development, and the clinical opportunities they may create across both advanced and early-stage settings. By refining target specificity and addressing resistance-associated cell-cycle rewiring, next-generation CDK inhibitors may reduce toxicity, enhance treatment durability, and enable more effective combination and sequencing strategies. Collectively, these advances promise to move breast cancer treatment beyond current CDK4/6 inhibition toward more precise, adaptable, and durable cell-cycle–directed therapy.
Date unavailable
Xin Li, Tong Chen, Wenjing Zhao, Jiaxing Li, Yifan Shang, Bing Chen, Lijuan Wang, Ning Zhang, Xiaoli Kong, Yiran Liang, Yaming Li, Chen Li, Dianwen Han, Xi Chen, Shan Jiang, Chao Yang, Dan Luo, Tingting Ma, Qifeng Yang
Triple-negative breast cancer (TNBC), characterized by aggressive behavior and poor prognosis, presents a formidable clinical challenge. Despite guideline endorsement of chemoimmunotherapy as a standard treatment in TNBC, durable responses remain rare, largely due to an immunologically “cold” tumor microenvironment (TME). Through integrated analysis, we identified the F-box protein FBXW5 as a tumor-intrinsic immunosuppressive regulator, whose expression is elevated in immunologically “cold” TNBC and correlates with dismal patient survival. Genetic knockdown of murine Fbxw5 suppressed tumor growth, reinvigorated CD8+ T cell–mediated antitumor immunity, and sensitized TNBC tumors to both single-agent and combined chemoimmunotherapy in preclinical models. Mechanistically, FBXW5 acts within the SKP1/CUL1/F-box protein E3 ligase complex to bind RIGI and MDA5, promoting their K27-linked polyubiquitination and subsequent SQSTM1-mediated autophagic degradation. This process blunts cytosolic RNA sensing and type I interferon signaling, thereby limiting CD8+ T cell infiltration and activation. Our findings establish FBXW5 as a master regulator of the “cold” TME, presenting a potential predictive biomarker and actionable therapeutic target for enhancing chemoimmunotherapy in TNBC.
Date unavailable
Chenjian Gu, Yili Fang, Yixuan Wang, Eric Tycksen, Gayathri Kondepati, Chuang Li, Kendrah O. Kidd, Jun Liu, Fumihiko Urano, Maria Lindahl, Anthony J. Bleyer, Srikanth Singamaneni, Zhao Sun, Ying Maggie Chen
Date unavailable
Fabiana Napolitano, Nisha Unni, Carlos L. Arteaga
Somatic alterations in the phosphoinositide 3-kinase (PI3K) pathway are frequent oncogenic drivers in cancer and are particularly relevant in estrogen receptor–positive breast cancer, where PI3K signaling integrates hormonal, growth factor, and metabolic inputs. Therapeutic targeting of PI3K has been limited by toxicity, pathway crosstalk, and adaptive resistance. Recent advances in structural and functional characterization of PIK3CA mutations have enabled the development of more selective inhibitors, including PI3K isoform–selective and emerging allosteric PI3Ka mutant–targeted compounds. These approaches aim to improve the therapeutic index while maintaining pathway inhibition. In parallel, combination strategies with endocrine therapy and CDK4/6 inhibitors have demonstrated clinical benefit in selected patient populations. However, responses are often transient owing to compensatory signaling and pathway reactivation. Additional metabolic and transcriptional adaptations further contribute to sustaining tumor cell survival. Overall, PI3K-targeted therapy is evolving along two complementary paths: increased mutant-selective inhibition to improve therapeutic index and broader pathway-level strategies designed to overcome adaptive resistance and achieve more durable responses. Ongoing efforts focus on optimizing combination strategies, enhancing development of predictive biomarkers, and improving therapeutic sequencing to achieve durable responses while minimizing toxicity.