Top read articles in the last 30 days
This list is updated daily and reflects the last month of access data. Articles older than two years will not be shown.
Abstract
Stem cell–derived β cells offer a promising approach for type 1 diabetes (T1D) treatment. However, the processes of graft infiltration and rejection by immune cells remain poorly understood in humans. In this study, autologous or allogeneic stem cell–derived islets (SC-islets) were transplanted in human immune system mice and analyzed 14 to 18 weeks later. Imaging mass cytometry revealed unique characteristics of SC-islet grafts, including a high percentage of glucagon+ cells and the presence of cysts and CD57+ enterochromaffin cells, features not typically observed in endogenous or transplanted allogeneic primary pancreatic islets. Allogeneic SC-islet grafts exhibited heavy immune infiltration, cell proliferation, and pro-fibrotic processes, whereas autologous grafts showed minimal infiltration and little fibrosis. In some mice, autologous T cells expressing islet antigen-reactive (IAR) T cell receptors (TCRs) were adoptively transferred. Three weeks after transfer, autologous grafts injected with IAR-TCR+ T cells showed negligible immune infiltration, even though IAR-TCR+ T cells were detected in the spleen. Under the conditions tested, human SC-islet grafts were not rejected by an autologous immune system, even in the presence of autoreactive T cells, pointing to several limitations that remain to be addressed for a model of spontaneous autologous SC-islet infiltration and destruction.
Authors
Camillo Bechi Genzano, Giorgia Zanetti, Qian Du, Daniel Traum, Deeksha Lahori, Grant M. Downes, Sakshi A. Bhatele, Xiaolan Ding, Kyle D. Apley, Rebuma Firdessa Fite, Matthew Ishahak, Enrique Eduardo Sanchez-Castro, Jeffrey R. Millman, Yiming Luo, Klaus H. Kaestner, Cory Berkland, Dieter Egli, Megan Sykes, Remi J. Creusot
Total views: 2596
Abstract
Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. These transcriptional changes were confirmed by orthogonal imaging techniques and biochemical assays. Single-nuclei RNA sequencing and spatial transcriptomics, both the first of their kind to our knowledge from Alport mice, showed that NAD+ supplementation restored FAO in proximal tubule cells. Finally, we also report, for the first time to our knowledge, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
Authors
Bryce A. Jones, Debora L. Gisch, Komuraiah Myakala, Amber Sadiq, Ying-Hua Cheng, Elizaveta Taranenko, Julia Panov, Kyle Korolowicz, Ricardo Melo Ferreira, Xiaoping Yang, Briana A. Santo, Katherine C. Allen, Teruhiko Yoshida, Xiaoxin X. Wang, Avi Z. Rosenberg, Sanjay Jain, Michael T. Eadon, Moshe Levi
Total views: 2595
Abstract
Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined, and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza, and SARS-CoV-2–driven pneumonia. Our analysis revealed highly pneumonia type–specific proteomic signatures, including COVID-19–specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V–domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry–driven autoantibody profiling in 2 independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.
Authors
Anna Semenova, Taylor A. Poor, Johannes B. Müller-Reif, Sai Rama Sridatta Prakki, Phillip Geyer, Martin Mück-Häusl, Rogan A. Grant, Luke Rasmussen, Lesca M. Holdt, Daniel Teupser, Matthias Mann, Ali Ö. Yildirim, Richard G. Wunderink, Alexander V. Misharin, Ben D. Singer, G.R. Scott Budinger, Theodore S. Kapellos, Herbert B. Schiller
Total views: 2557
Abstract
Solute carrier family 39, member 8 (SLC39A8), is a transmembrane transporter that mediates the cellular uptake of zinc, iron, and manganese (Mn). Human genetic studies document the involvement of SLC39A8 in Mn homeostasis, brain development, and function. However, the role and pathophysiological mechanisms of SLC39A8 in the central nervous system remain elusive. We generated Slc39a8 neuron-specific knockout (Slc39a8-NSKO) mice to study SLC39A8 function in neurons. The Slc39a8-NSKO mice displayed markedly decreased Mn levels in the whole brain and brain regions, especially the cerebellum. Radiotracer studies using 54Mn revealed that Slc39a8-NSKO mice had impaired brain uptake of Mn. Slc39a8-NSKO cerebellums exhibited morphological defects and abnormal dendritic arborization of Purkinje cells. Reduced neurogenesis and increased apoptotic cell death occurred in the cerebellar external granular layer of Slc39a8-NSKO mice. Brain Mn deficiency in Slc39a8-NSKO mice was associated with motor dysfunction. Unbiased RNA-Seq analysis revealed downregulation of key pathways relevant to neurodevelopment and synaptic plasticity, including cAMP signaling pathway genes. We further demonstrated that Slc39a8 was required for the optimal transcriptional response to the cAMP-mediated signaling pathway. In summary, our study highlighted the essential roles of SLC39A8 in brain Mn uptake and cerebellum development and functions.
Authors
Eun-Kyung Choi, Luisa Aring, Yujie Peng, Adele B. Correia, Andrew P. Lieberman, Shigeki Iwase, Young Ah Seo
Total views: 2529
Abstract
Transcriptional reprogramming has an important role in kidney glomerular disease. Using in vivo murine models of podocyte injury, we studied the roles of the FOXC2 and WT1 transcription factors (TFs) in podocyte injury. Podocytes are a crucial cell type of glomeruli, the filtration units of each nephron. Podocyte injury is often the incipient event leading to chronic kidney disease. It is well established that the TFs FOXC2 and WT1 are required in podocytes to maintain the glomerular filtration barrier. Their role in the response to injury is less well understood. Here, we tested the hypothesis that FOXC2 and WT1 act together to mediate transcriptional reprogramming in response to podocyte injury. Similarly to that of WT1, genome-wide FOXC2 binding to target genes is dynamic during the course of injury, initially increasing, but late in injury there is a dramatic decrease in FOXC2 expression and in its binding to target genes. Podocyte-specific inactivation of FoxC2 or Wt1 in adult mice limits the transcriptional response to injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Thus, reprogramming the transcriptome involves dynamic changes in the binding of FOXC2 and WT1 to their target genes during a reparative injury response.
Authors
Sandrine Ettou, Anya Greenberg, Sangyoon Lee, Arjun Rajesh, Liang Sun, Nahid Tabibzadeh, Haruka Oishi, Ran Konoe, Phillip J. McCown, Sean Eddy, Victoria Driscoll, Tomoya Miyoshi, Ken Hiratsuka, Jason Lam, R. Sathish Srinivasan, Youngsook L. Jung, Biju Isaac, Mingwei Sun, Mary E. Taglienti, Keith Keller, Hong Chen, Matthias Kretzler, Astrid Weins, Ryuji Morizane, Shira Rockowitz, Valerie A. Schumacher, Dongwon Lee, Jordan A. Kreidberg
Total views: 2470
Abstract
Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR’877), a potentially novel PD-1–targeted immunocytokine that fuses a high-affinity anti–PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1+ T cells, enhancing proliferation and activation of antigen-experienced CD8+ and CD4+ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR’877 activates STAT5 signaling in PD-1+ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR’877 accelerated viral clearance and induced robust antitumor immunity by expanding cytotoxic CD8+ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed anti–PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR’877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.
Authors
Isaraphorn Pratumchai, Marie Bernardo, Julien Tessier, Jaroslav Zak, Kristi L. Marquardt, Joon Sang Lee, Maheeka Bimal, AHyun Choi, Anthony M. Byers, Mikielia G. Devonish, Roberto Carrio, Dan Lu, Stella Martomo, Jeegar Patel, Yu-an Zhang, Ingeborg M. Langohr, Virna Cortez-Retamozo, Dinesh S. Bangari, Angela Hadjipanayis, Xiangming Li, Valeria R. Fantin, Donald R. Shaffer, John R. Teijaro
Total views: 2369
Abstract
BK polyomavirus–associated nephropathy (BKVN) adversely impacts kidney allograft survival and often mimics acute T cell–mediated rejection (TCMR), confounding diagnosis and management. To address this conundrum, we performed unbiased RNA sequencing of urinary cells matched to biopsies classified as BKVN with intragraft inflammation (BKVN-P), BKVN without inflammation (BKVN-N), TCMR, or no rejection (NR). BKVN-N displayed dominant host DNA replication, cell cycle, and repair programs, while BKVN-P samples exhibited expansive innate immune activation, antigen presentation, chemokine upregulation, and epithelial injury. Both BKVN subtypes shared signatures of T cell exhaustion and mature and tolerogenic dendritic cell activation but differed in immune orientation — Th1 predominance in BKVN-N versus Treg and CD8 enrichment in BKVN-P. Compared with TCMR samples, BKVN-P lacked robust TCR/CD28 signaling and was enriched for viral and innate modules; BKVN-N lacked alloimmune activation. B cell exhaustion characterized BKVN-N, while BKVN-P displayed robust B cell activation with metabolic downregulation. A ratiometric urinary cell biomarker, CXCL10 mRNA/CD3E mRNA, distinguished both BKVN subtypes from TCMR with diagnostic accuracy, replicated by quantitative reverse transcription PCR for clinical translation, and confirmed in an independent cohort. These findings demonstrate the utility of urinary cell transcriptomics for resolving viral injury from alloimmunity, enabling precision diagnostics and targeted immunomodulation in kidney transplantation.
Authors
Franco B. Mueller, Carol Li, Darshana M. Dadhania, Surya V. Seshan, Thalia Salinas, Vijay K. Sharma, Jenny Z. Xiang, Hans H. Hirsch, Thangamani Muthukumar, Manikkam Suthanthiran
Total views: 2229
Abstract
Human CD4+ T cells utilize nutrients, including lipids, to support their activation and polarization. Considering the pivotal role of lipoproteins in lipid transport, we reasoned that lipoprotein uptake and processing could effect CD4+ T cell function. Here, we demonstrate that activation of human CD4+ T cells induced expression of LDL receptor (LDLR) to facilitate LDLR-mediated endocytosis of LDL. Degradation of surface LDLR on CD4+ T cells with PCSK9 hampered activation and proliferation of the cells. Lipoprotein deprivation or blocking of lysosomal cholesterol egress impaired activation of mechanistic target of rapamycin complex 1 (mTORC1), affecting CD4+ T cell activation and proliferation. Furthermore, lipoprotein deprivation of cultured primary CD4+ T cells lead to reduced expression of c-MAF and FOXP3, key transcription factors for IL-10, accompanied by reduced IL-10 secretion. The pivotal role of LDLR-mediated lipoprotein uptake for mTORC1 activity, c-MAF and FOXP3 expression, and IL-10 secretion was confirmed using LDLR-dysfunctional CD4+ T cells from patients with homozygous familial hypercholesterolemia. Our study offers valuable insights into the lipoprotein metabolism of human CD4+ T cells and their reliance on the LDLR pathway for activation and polarization, a feature that may be leveraged to modulate CD4+ T cell function.
Authors
Angela Markovska, Niels S. van Heusden, Dagmar Duijzer, Alejandra Bodelón, Greta Rogani, Enric Mocholi, Edwin C.A. Stigter, Can Gulersonmez, Sander Kooijman, Leonie Van der Zee, Monique T. Mulder, Jeanine E. Roeters van Lennep, Patrick C.N. Rensen, Jorg van Loosdregt, Sebastiaan J. Vastert, Noam Zelcer, Marianne Boes, Henk S. Schipper
Total views: 2201
Abstract
Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA), yet its mechanism remains unclear. RA synovium exhibits metabolic shift, characterized by upregulated glycolysis and enhanced lactate production. In this study, we elucidated the mechanism underlying the roles of lactate metabolism and protein lactylation in RA pathology. In patients with RA, both lactate production and protein lactylation were elevated and showed a positive correlation with clinical disease activity. These changes were further implicated in driving synovial proliferation. Among the lactylated proteins, Cysteine-rich intestinal protein 1 (CRIP1) exhibited a marked increase in modification and played a central role in promoting synovial proliferation. Mechanistically, CRIP1 underwent MOF-mediated lactylation in RA synovial fibroblasts. Lactylated CRIP1 hijacked the cell-cycle regulator p21, disrupting its interaction with cyclin-dependent kinase 2 (CDK2), thereby facilitating the G1/S phase transition. Functionally, AAV-mediated delivery of a lactylation-deficient CRIP1 K49R significantly reduced synovial proliferation compared with WT CRIP1. Peptide-based interventions targeting CRIP1 K49 lactylation effectively inhibited synovial hyperplasia and disease severity in both Collagen II–induced arthritis (CIA) and humanized NSG chimeric models. Collectively, CRIP1 protein lactylation drives synovial proliferation in RA by hijacking p21 from CDK2, thereby facilitating cell cycle progression. Targeting this pathway may serve as a promising strategy for RA.
Authors
Meican Ma, Yu Zhou, Qianlin Li, Zhao Wang, Shangqi Guan, Xiaoxue Wang, Han Zhao, Zhenke Wen, Ting Liu, Fenghong Yuan
Total views: 2040
Abstract
Tumor cells are constantly confronted with nutrient deprivation; however, the effect of serum starvation on the remodeling of endosomal compartments and extracellular vesicles (EVs) in tumor cells remains unclear. Here, we found that serum starvation pronouncedly promotes multivesicular body (MVB) biogenesis, EV formation, and cargo selection. Specifically, by generating a constitutively active Rab5Q79L mutant to induce the enlargement of MVB, we revealed for the first time to our knowledge that ANXA3 is sorted into intraluminal vesicles (ILVs) of MVB. Mechanistically, we confirmed that serum starvation regulates the endosomal sorting complex required for transport–associated (ESCRT-associated) protein ALG-2 interacting protein X (ALIX), which recruits ESCRT-III to MVB and binds to annexin A3 (ANXA3) to mediate its sorting into ILVs of MVB. Our study highlights that serum starvation promotes an ALIX-dependent ESCRT-III recruitment pathway, which loads protumor ANXA3 cargo to exert a profound effect on tumor progression.
Authors
Xueqiang Peng, Jiaxing Liu, Guolong Zeng, Yafei Xiao, Zhixiong Hao, Guangpeng He, Hongyuan Jin, Yu Gao, Shilei Tang, Shibo Wei, Yan Li, Yifan Yu, Liang Yang, Hangyu Li
Total views: 2016
