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Abstract
BACKGROUND. Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS. We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS. Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS. Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING. This work is the result of NIH funding.
Authors
Narges Alipanah-Lechner, Lucile Neyton, Pratik Sinha, Carolyn Leroux, Kim Bardillon, Sidney A. Carrillo, Suzanna Chak, Olivia Chao, Taarini Hariharan, Carolyn Hendrickson, Kirsten Kangelaris, Charles R. Langelier, Deanna Lee, Chelsea Lin, Kathleen Liu, Liam Magee, Angelika Ringor, Aartik Sarma, Emma Schmiege, Natasha Spottiswoode, Kathryn Sullivan, Melanie F. Weingart, Andrew Willmore, Hanjing Zhuo, Angela J. Rogers, Kathleen A. Stringer, Michael A. Matthay, Carolyn S. Calfee
Abstract
GATA6 is a master regulator of differentiation in the pancreas and its expression levels determine the two main molecular subtypes of pancreatic cancer. High GATA6 contributes to the “classical” pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulate GATA6 expression remain elusive. Here we report that the oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilizes JUNB protein while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Up-regulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.
Authors
Zheng Zhong, Xinang Cao, Pei-Ju Liao, Raman Sethi, Jeffrey A. Klomp, Clint A. Stalnecker, Jinmiao Chen, Yue Wan, Channing J. Der, David M. Virshup
Abstract
During vascular injury, platelets are essential for halting bleeding and recruiting neutrophils to prevent microbial invasion. However, in antibody-mediated autoimmune diseases occurring without vascular damage, neutrophils infiltrate tissues and contribute to pathology. Here, we investigated whether the dependence of neutrophils on platelets is conserved in the context of antibody-driven inflammation. Using human cells from individuals with rheumatoid arthritis and a microfluidic system mimicking physiological shear over IgG-containing immune complexes, we demonstrate that despite expressing Fc receptors, neutrophils require platelets to stably adhere to immune complexes under flow. Platelet FcγRIIA binding was critical for resisting shear stress, while neutrophils used FcγRIIA and FcγRIIIB for immune complex recognition. Platelet P-selectin binding to neutrophil PSGL-1 was essential for recruitment, whereas Mac-1 was dispensable. In a mouse model of autoantibody-mediated arthritis, intravital imaging confirmed that neutrophil recruitment critically relies on PSGL-1. Importantly, expression of FcyRIIA aggravated arthritis, and blockade of PSGL-1 in these mice, but not of Mac-1, abrogated both the platelet and neutrophil interactions and disease. These findings identify key molecular interactions in platelet–neutrophil cooperation and reveal that platelets are essential enablers of FcR-mediated neutrophil adhesion in antibody-driven inflammation.
Authors
Marie Bellio, Isabelle Allaeys, Etienne Doré, Myriam Vaillancourt, Tania Lévesque, Mélina Monteil, Nicolas Vallières, Philippe Desaulniers, Nicolas Bertrand, Valance A. Washington, Yotis Senis, Steve Lacroix, Paul Fortin, Clémence Belleannée, Eric Boilard
Abstract
The role of CARD9 in the pathogenesis of various chronic fungal infections has been established; however, the precise mechanisms underlying the pathobiology of these infections remain unclear. We aimed to investigate the specific cellular mechanisms by which CARD9 deficiency contributes to the pathogenesis of chronic fungal infections. Using single-cell RNA sequencing (scRNA-seq), we analyzed the immune cell profiles in skin lesions from both murine and human samples. We focused on macrophage differentiation and signaling pathways influenced by CARD9 deficiency. We found that CARD9 deficiency promotes the differentiation of TREM2high macrophages following fungal stimulation, impairing their antifungal functions and inducing exhaustion-like T helper 1 (Th1) cells. Mechanistically, the NF-κB pathway activation was restricted in CARD9-deficient macrophages, leading to enhanced CREB activation, which in turn exerted a positive regulatory effect on Trem2 expression by activating C/EBPβ. Notably, targeting TREM2 enhanced the antifungal immune response in vivo and in vitro, thereby alleviating the severity of CARD9-deficient subcutaneous dematiaceous fungal infection. Our findings highlight the important role of CARD9 in regulating cutaneous antifungal immunity and identify potential targets for immunotherapy in chronic dematiaceous fungal infections.
Authors
Lu Zhang, Zhichun Tang, Yi Zhang, Wenjie Liu, Haitao Jiang, Li Yu, Kexin Lei, Yubo Ma, Yang-xin Fu, Ruoyu Li, Wenyan Wang, Fan Bai, Xiaowen Wang
Abstract
Emerging evidence demonstrates that chronic stress alters immunological, neurochemical and endocrinological functions, thereby promoting tumor progression. However, the underlying metabolic mechanism of chronic stress in tumor progression is still elusive. Using multi-omics analysis, we found that aminopeptidase N (ANPEP) was upregulated in tumors with chronic restraint, associating with the reprogramming of amino acid metabolism. Functional assays revealed that ANPEP promoted liver cancer growth and metastasis. Knockdown of ANPEP blocked chronic stress-induced liver cancer progression. Chronic stress-induced glucocorticoids promoted nuclear receptor subfamily 3 group C member 1 (NR3C1) nuclear translocation to activate ANPEP transcription by directly binding to its promoter. Furthermore, ANPEP promotes glutathione synthesis, subsequently inhibiting reactive oxygen species (ROS)-induced ferroptosis. Mechanistically, ANPEP interacted with solute carrier family 3 member 2 (SLC3A2) to block membrane associated ring-CH-type finger 8-mediated (MARCH8-mediated) lysosome-dependent degradation of SLC3A2, promoting intracellular L-cystine transport, thereby increasing glutathione synthesis. The combination of ANPEP silencing and sorafenib treatment showed a synergistic effect in inhibiting liver cancer progression. Finally, clinical data and mouse models demonstrated that chronic stress drove liver tumor progression via ANPEP-regulated SLC3A2. These findings reveal unanticipated communication between chronic stress and metabolic reprogramming during liver cancer progression, providing potential therapeutic implications for liver cancer.
Authors
Yongkang Wu, Yankun Zhang, Xiaojia Shi, Mengting Wu, Min Sun, Ying Feng, Wenmeng Ma, Xiule Jiang, Dingqi Fei, Mingjian Zhao, Zhuanchang Wu, Chunyang Li, Xiaohong Liang, Lifen Gao, Chunhong Ma, Xuetian Yue
Abstract
BACKGROUND. Axonal degeneration is believed to be an early hallmark of Alzheimer’s disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using diffusion MRI-derived Axonal Density Index (dMRI-ADI). METHODS. Longitudinal dMRI, CSF and PET data from the ADNI were analyzed, including 117 cognitively normal (CN) and 88 impaired (CI) subjects, consisting of 74 mild cognitive impairment (MCI) and 14 AD individuals. Linear mixed-effects models examined group differences as well as associations between baseline and longitudinal changes in ADI, CSF or PET biomarkers and clinical outcomes. Results derived from larger CSF (n=527) and PET (tau-PET: n=870; amyloid-PET: n=1581) data were also presented. RESULTS. Compared to CN, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (p<10–⁶). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: p=0.03; CDR-SB: p<10–⁴), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: p=0.001; CDR-SB: p<10–¹²). Compared to CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; an association observed only with amyloid-PET, but not CSF biomarkers. CONCLUSION. Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring. TRIAL REGISTRATION. ClinicalTrials.gov NCT00106899. FUNDING. This work was supported by the National Institute on Aging IRP.
Authors
Zhaoyuan Gong, John P. Laporte, Alexander Y. Guo, Murat Bilgel, Jonghyun Bae, Noam Y. Fox, Angelique de Rouen, Nathan Zhang, Aaliya Taranath, Rafael de Cabo, Josephine M. Egan, Luigi Ferrucci, Mustapha Bouhrara
Abstract
Epstein-Barr virus (EBV) is of growing interest for its potential role in neurodegenerative diseases such as multiple sclerosis (MS) and its possible utility as a therapeutic target in herpesvirus-associated chronic diseases. The effects of brincidofovir (BCV) on EBV reactivation were evaluated in vitro using EBV-infected spontaneous lymphoblastoid cell lines (SLCLs) and peripheral blood mononuclear cells (PBMCs) derived from MS patients and healthy controls. In addition, a B lymphoblastoid cell line and PBMCs from common marmosets (Callithrix jacchus) naturally infected with an EBV-related gammaherpesvirus (Callitrichine herpesvirus 3, CalHV-3) were used to measure BCV efficacy in a nonhuman primate model. BCV significantly inhibited gammaherpesvirus reactivation, with decreased lytic and latent viral transcript expression. These results suggest that BCV may be a useful antiviral for inhibiting EBV activity in MS patients. Additionally, this work further validates the utility of CalHV-3 in marmosets as a translational model for the investigation of successful EBV-targeting therapeutics.
Authors
Abaigeal Donaldson, Madeleine R. Druker, Maria Chiara Monaco, Emily H. Stack, Paige Zimmerman, Amanda Lee, Izabela Bialuk, William Frazier, Irene Cortese, Heather Narver, Masatoshi Hazama, Fuminori Yoshida, Xiaofan Li, Laurie T. Krug, Stacey L. Piotrowski, Steven Jacobson
Abstract
Acute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. To identify additional drivers of leukemogenesis, we analyzed sequencing data from 1,727 unique individual AML patients, which revealed mutations in ubiquitin ligase family genes in 11.2% of adult AML samples with mutual exclusivity. The SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase complex gene, FBXO11, was the most significantly downregulated gene of the SCF complex in AML. We found that FBXO11 interacts with and catalyzes K63-linked ubiquitination of LONP1 in the cytosol, to promote LONP1 entry into mitochondria. We show that depletion of FBXO11 or LONP1 reduces mitochondrial respiration through impaired LONP1 chaperone activity to assemble electron transport chain Complex IV. Reduced mitochondrial respiration secondary to FBXO11 or LONP1 depletion imparted myeloid-biased stem cell properties in primary CD34+ hematopoietic stem and progenitor cells (HSPC) in vitro. In a human xenograft model, depletion of FBXO11 cooperated with AML1-ETO and mutant KRASG12D to generate serially transplantable AML. Our findings suggest that reduced FBXO11 cooperates to initiate AML by priming HSPC for myeloid-biased self-renewal through attenuation of LONP1-mediated regulation of mitochondrial respiration.
Authors
Hayle Kincross, Ya-Chi Angela Mo, Xuan Wang, Linda Chang, Gerben Duns, Franziska Mey, Jihong Jiang, Zurui Zhu, Naomi Isak, Harwood Kwan, Tammy T.Y. Lau, T. Roderick Docking, Pranav Garg, Jessica Tran, Shane Colborne, Se-Wing Grace Cheng, Shujun Huang, Nadia Gharaee, Elijah Willie, Jeremy D.K. Parker, Joshua Bridgers, Davis Wood, Ramon I. Klein Geltink, Gregg B. Morin, Aly Karsan
Abstract
Authors
Antonio Carlos Tallon-Cobos, Konstantinos Vazaios, Piotr Waranecki, Marliek van Hoesel, Annelisa M. Cornel, Benjamin Schwalm, Norman Mack, Ella de Boed, Jasper van der Lugt, Stefan Nierkens, Marcel Kool, Eelco W. Hoving, Dennis S. Metselaar, Esther Hulleman
Abstract
Authors
Alexander M. Loiben, Wei-Ming Chien, Ashley McKinstry, Dania Ahmed, Matthew C. Childers, Michael Regnier, Charles E. Murry, Kai-Chun Yang
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