Top read articles in the last 30 days
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Abstract
Pulmonary fibrosis is frequently accompanied by pulmonary hypertension, which can occur disproportionate to the extent of fibrosis, suggesting a fibrosis-independent vascular remodeling process. Here, we demonstrated that plasma growth differentiation factor 15 (GDF15) is elevated across diverse fibrotic lung disease subtypes and correlates with markers of elevated right heart pressures but not pulmonary function indices, indicating a possible link to endothelial cell dysfunction. To investigate the import of endothelial GDF15 as a modifier of lung fibrosis pathogenesis, we generated endothelial cell–specific Gdf15-KO mice, which showed protection from bleomycin-induced lung injury and fibrosis, with preserved lung function. RNA-seq of human pulmonary microvascular endothelial cells revealed altered expression of barrier-regulatory genes in GDF15-deficient endothelial cells compared with controls. Functional studies confirmed that GDF15 knockdown attenuates thrombin-induced barrier disruption by reducing cytosolic Ca2+ responses. Together, these findings implicate endothelial GDF15 as a modifier of vascular permeability and Ca2+ signaling and a contributor to lung injury and fibrosis.
Authors
Kristen Raffensperger, Marta Bueno, Brian J. Philips, Megan Miller, Máté Katona, Shuai Yuan, Adriana Estrada-Bernal, Byron Chuan, Pavan Suresh, Stephanie Taiclet, Scott Hahn, Yingze Zhang, Jonathan K. Alder, Seyed Mehdi Nouraie, Daniel J. Kass, Oliver Eickelberg, Adam C. Straub
Total views: 4244
Abstract
Modic type 1 and 2 changes (MC-1 and MC-2) are highly prevalent in individuals with chronic low back pain, yet the cellular and molecular mechanisms underlying vertebral endplate degeneration remain poorly defined. Here, we report that osteoclastogenesis is markedly elevated in MC-1 and MC-2 lesions compared with MC-3 lesions, suggesting an active role for osteoclasts in the early stages of degeneration. Using a lumbar spine instability (LSI) mouse model, we demonstrate enhanced osteoclast activity in degenerating endplates. RNA sequencing of mononuclear cells isolated from the endplate and adjacent subchondral bone identified Gdf15 as a potential upstream regulator of this process. Conditional knockout of Gdf15 in monocytes reduced osteoclast formation, aberrant CD31hiEmcnhi angiogenesis, and pain-associated neurogenesis, ultimately mitigating endplate degeneration and mechanical allodynia. Mechanistically, GDF15 promoted the fusion of preosteoclasts by modulating the expression of Rho family small GTPases. In a humanized GDF15 knockin mouse model, therapeutic neutralization of GDF15 led to a reduction in osteoclast burden, improved endplate structure, and attenuated pain behavior. Together, these findings uncover a previously unrecognized role for GDF15 in driving osteoclast-mediated endplate degeneration and highlight its potential as a therapeutic target for the treatment of endplate-related chronic low back pain.
Authors
Xiaoqun Li, Jinhui Wu, Qingjie Kong, Miao Hu, Yuhong Li, Ziheng Wei, Heng Jiang, Xuhui Zhou, Jun Ma
Total views: 3869
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is a global health concern with limited interventions. While the role of gut bacteria in MASLD has been extensively studied, the contribution of gut fungi remains largely unexplored. This study investigates the impact of fungal dysbiosis and the role of CARD9, a key adaptor protein in fungal sensing on gut-liver axis dysfunction in MASLD. Patients with advanced liver fibrosis exhibited distinct mycobiota profiles. Using a Card9-deficient mouse model subjected to high-fat, high-glucose/-fructose feeding, we observed exacerbated liver injury and fibrosis accompanied by fungal dysbiosis, paralleling our findings in human patients. Beyond its established expression in myeloid cells, CARD9 was also detected in intestinal enterocytes where its expression was diminished under metabolic stress. Intestinal organoids with CARD9 inhibition had reduced expression of antimicrobial Reg3g, the tight junction protein ZO-1, and the antifungal enteroendocrine hormone PYY. These findings suggest that CARD9 maintains gut barrier integrity, preventing microbial translocation and subsequent liver injury and fibrosis. Our results provide insights into the interplay between fungal dysbiosis, gut barrier dysfunction, and MASLD, and identify CARD9 as a key protein within this axis.
Authors
Vijay Pandyarajan, So Yeon Kim, Takashi Tsuchiya, Selena Liu, Sadam H. Bhat, Jieun Kim, David M. Underhill, Mazen Noureddin, Shelly C. Lu, Ekihiro Seki
Total views: 3842
Abstract
BACKGROUND Inhibition of Bruton’s tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODS Sixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTS Common adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5–14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton’s tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSION Ibrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATION ClinicalTrials.gov NCT03525925.FUNDING NIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.
Authors
Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H. Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C. Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A. Shah, Anne M. Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W. Blaser, William E. Carson III
Total views: 3598
Abstract
Despite the widespread use of adenovirus, mRNA, and protein-based vaccines during the COVID-19 pandemic, their relative immunological profiles and protective efficacies remain incompletely defined. Here, we compared antigen kinetics, innate and adaptive immune responses, and protective efficacy following Ad5, mRNA, and protein vaccination in mice. Ad5 induced the most sustained antigen expression, but mRNA induced the most potent IFN responses, associated with robust antigen presentation and costimulation. Unlike Ad5 vaccines, which were hindered by preexisting vector immunity, mRNA vaccines retained efficacy after repeated use. As a single-dose regimen, Ad5 vaccines elicited higher immune responses. However, as a prime-boost regimen, and particularly in Ad5 seropositive mice, mRNA vaccines were more immunogenic than the other vaccine platforms. These findings highlight strengths of each vaccine platform and underscore the importance of host serostatus in determining optimal vaccine performance.
Authors
Bakare Awakoaiye, Shiyi Li, Sarah Sanchez, Tanushree Dangi, Nahid Irani, Laura Arroyo, Gabriel Arellano, Shadi Mohammadabadi, Malika Aid, Pablo Penaloza-MacMaster
Total views: 3553
Abstract
BACKGROUND. Despite antiretroviral therapy (ART), people with HIV (PWH) are at heightened risk for insulin resistance (IR) and type 2 diabetes (T2D). Subcutaneous adipose tissue (SAT) fibrosis contributes to metabolic disease, but its role in IR among PWH is unknown. We investigated the relationship between SAT fibrosis and IR in PWH, along with transcriptional signatures to distinguish it from SAT fibrosis due to obesity. METHODS. We analyzed body composition and SAT fibrosis (hydroxyproline) in 46 PWH and 74 people without HIV (PWoH), excluding individuals with T2D. We examined fibrosis-related gene transcription in the SAT using a targeted panel and measured plasma endotrophin, a marker of extracellular matrix (ECM) remodeling. RESULTS. PWH had substantially more SAT fibrosis than PWoH, notably in non-obese individuals. Moreover, SAT fibrosis in these PWH was strongly associated with IR, independently of prior legacy ART or ongoing integrase strand inhibitor treatment. This SAT fibrosis was highlighted by a distinct transcriptional pattern marked by upregulation of COL14A1, key immune-related genes (e.g., CCL4, NLRP3), and pathways governing ECM remodeling and immune activation, as well as downregulation of thermogenic, lipid metabolic, and insulin signaling pathways. Plasma endotrophin levels were also elevated in PWH and correlated independently with SAT fibrosis. CONCLUSION. SAT fibrosis was associated with IR independent of obesity in PWH and was mirrored by circulating endotrophin levels, offering a plausible noninvasive biomarker for early intervention. The distinct transcriptional signature of HIV-associated SAT fibrosis highlights candidate mechanisms that may underlie metabolic risk and offer therapeutic avenues in this population.
Authors
Diana L. Alba, Alaa Abdellatif, Moon K. Choi, Stephen M. Brown Mayfield, Thuy An T. Pham, David I. Berrios, Antonio E. Rodriguez, Marin Ewing, Tony R. Figueroa, Judy Gonzalez-Vargas, Ningyan Zhang, Zhiqiang An, Dawei Bu, Steven G. Deeks, Philipp E. Scherer, Peter W. Hunt, Suneil K. Koliwad
Total views: 3492
Abstract
Given the central role of peroxisomes in lipid metabolism and redox homeostasis, we hypothesized that peroxisomal activity is critical for sustaining β cell function and identity. Pex5 deletion models were employed to investigate loss of peroxisomal function on glucose-stimulated insulin secretion (GSIS), oxidative stress, and β cell maturity markers. Peroxisome deficiency in male mice resulted in elevated GSIS. Glucose intolerance developed despite increased insulin secretion. Ion mobility mass spectrometry revealed oxidation of insulin proteins, and a truncated insulin 2-derived peptide, in islets from mice with a tissue-specific deficiency in peroxisomes. Peroxisome loss of function increased multiple markers of oxidative stress, including altered metabolite profiles, lipid peroxidation, and protein carbonylation. These findings reveal that increased secretion of oxidized insulin protein is insufficient to regulate whole-body glucose homeostasis. Peroxisome deficiency also reduced markers of β cell maturity. Based on these outcomes, we identified the peroxisome organelle as a key regulatory component of glucose homeostasis by protecting insulin from oxidative modification and degradation and by supporting maintenance of mature β cells.
Authors
J. Jason Collier, Caroline R. Cothern, Maggie P. Ducote, Thomas M. Martin, Melissa A. Linden, Robert C. Noland, David H. Burk, Samuel D. Dupuy, Michael D. Karlstad, Krisztian Stadler, Sarah S. Hirschbeck, Thanh D. Do, Anastasia Coldren, Marcela Brissova, Teayoun Kim, Kirk M. Habegger, Sujoy Ghosh, Zane A. Vickery, Qudus Sarumi, Shawn R. Campagna, Susan J. Burke
Total views: 3356
Abstract
High dietary salt intake elevates blood pressure and drives multiorgan damage. However, the molecular programs underlying progressive organ injury remain poorly defined. Here, we present a longitudinal multiorgan transcriptomic atlas of salt-induced hypertensive injury. We profiled kidney cortex, kidney medulla, heart, and liver across 4 stages, spanning early hypertension to advanced pathology in Dahl salt-sensitive rats. We identified dynamic and tissue-specific molecular trajectories, including a shared early proliferative response that converges on proinflammatory and fibrotic remodeling. Notably, we uncovered compartment-specific renal responses, showing that the cortex and medulla, despite their proximity, follow distinct molecular trajectories during disease progression. We further identified 79 stage- and tissue-specific transcription factors that drive gene expression dynamics in salt-induced hypertensive injury. Integration with human genome-wide association studies revealed conserved pathways in endocrine signaling, ion transport, lipid metabolism, and detoxification, establishing cross-species relevance and highlighting mechanistic targets of clinical importance. Compound-transcriptome analysis revealed stage- and organ-specific therapeutic opportunities, prioritizing kinase and epigenetic modulators as candidates to rebalance maladaptive gene programs. Overall, this study provides a resource for understanding molecular mechanisms from early salt-induced hypertension to tissue-specific injury and underscores the need for precision interventions.
Authors
Ratnakar Tiwari, Olha Kravtsova, Lashodya V. Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Steven Didik, Ruslan Bohovyk, Daria V. Ilatovskaya, Oleg Palygin, Alexander Staruschenko
Total views: 3355
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cells are a leading immunotherapy for refractory B cell malignancies; however, their effect is limited by toxicity and incomplete efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success; however, their clinical relevance to CAR T cell therapy remains unknown.METHODS We retrospectively analyzed CAR T cell survival and complications based on infusion time at 2 geographically distinct hospitals: Washington University School of Medicine in St. Louis, Missouri, USA (n = 384) and Oregon Health & Science University in Portland, Oregon, USA (n = 331) between January 2018 and March 2025. The primary outcome was 90-day overall survival (OS). Secondary outcomes included event-free survival (EFS), cytokine release syndrome (CRS), immune cell–associated neurotoxicity syndrome (ICANS), ICU admission, shock, respiratory failure, and infection. We quantified the independent relationship between infusion time and outcomes using multivariable mixed-effects logistic regression and time-to-event models, adjusting for patient, oncologic, and treatment characteristics.RESULTS The therapeutic index of CAR-T cells inversely correlated with the timing of administration, with later infusions associated with lower effectiveness and more adverse outcomes. For each hour that CAR T cell treatment was delayed, the adjusted odds ratio (aOR) of 90-day mortality increased by 24% (aOR 0.76; 95% CI 0.64–0.88, P = 0.001), severe neurotoxicity by 17% (P = 0.023), and mechanical ventilation by 27% (P = 0.026). These temporal patterns were most pronounced in patients receiving CD19-targeting CAR T cell products. In contrast, we did not find an association between infusion time and severe CRS (aOR 0.99; 95% CI, 0.75–1.27; P = 0.92).CONCLUSION Time of day is a potent and easily modifiable factor that could optimize CAR T cell clinical performance.
Authors
Patrick G Lyons, Emily Gill, Prisha Kumar, Melissa Beasley, Brenna Park-Egan, Zulfiqar A. Lokhandwala, Katie M. Lebold, Brandon Hayes-Lattin, Catherine L. Hough, Nathan Singh, Guy Hazan, Huram Mok, Janice M. Huss, Colleen A. McEvoy, Jeffrey A. Haspel
Total views: 3324
Abstract
Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.
Authors
Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E. Mitch, Sandhya S. Thomas
Total views: 3153
