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Circulation Nov 2023Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share similar clinical manifestations, including cardiovascular complications, suggesting... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share similar clinical manifestations, including cardiovascular complications, suggesting similar underlying immunopathogenic processes. Aberrant neutrophil activation may play a crucial role in the shared pathologies of KD and MIS-C; however, the associated pathogenic mechanisms and molecular drivers remain unknown.
METHODS
We performed a single-cell meta-analysis of neutrophil activation with 103 pediatric single-cell transcriptomic peripheral blood mononuclear cell data across 9 cohorts, including healthy controls, KD, MIS-C, compared with dengue virus infection, juvenile idiopathic arthritis, and pediatric celiac disease. We used a series of computational analyses to investigate the shared neutrophil transcriptional programs of KD and MIS-C that are linked to systemic damage and cardiac pathologies, and suggested Food and Drug Administration-approved drugs to consider as KD and MIS-C treatment.
RESULTS
We meta-analyzed 521 950 high-quality cells. We found that blood signatures associated with risks of cardiovascular events are enriched in neutrophils of KD and MIS-C. We revealed the expansion of CD177 neutrophils harboring hyperactivated effector functions in both KD and MIS-C, but not in healthy controls or in other viral-, inflammatory-, or immune-related pediatric diseases. KD and MIS-C CD177 neutrophils had highly similar transcriptomes, marked by conserved signatures and pathways related to molecular damage. We found the induction of a shared neutrophil expression program, potentially regulated by SPI1 (Spi-1 proto-oncogene), which confers enhanced effector functions, especially neutrophil degranulation. CD177 and shared neutrophil expression program expressions were associated with acute stages and attenuated during KD intravenous immunoglobulin treatment and MIS-C recovery. Network analysis identified hub genes that correlated with the high activation of CD177 neutrophils. Disease-gene association analysis revealed that the KD and MIS-C CD177 neutrophils' shared expression program was associated with the development of coronary and myocardial disorders. Last, we identified and validated TSPO (translocator protein) and S100A12 (S100 calcium-binding protein A12) as main molecular targets, for which the Food and Drug Administration-approved drugs methotrexate, zaleplon, metronidazole, lorazepam, clonazepam, temazepam, and zolpidem, among others, are primary candidates for drug repurposing.
CONCLUSIONS
Our findings indicate that CD177 neutrophils may exert systemic pathological damage contributing to the shared morbidities in KD and MIS-C. We uncovered potential regulatory drivers of CD177 neutrophil hyperactivation and pathogenicity that may be targeted as a single therapeutic strategy for either KD or MIS-C.
Topics: Humans; Child; Mucocutaneous Lymph Node Syndrome; Neutrophil Activation; Leukocytes, Mononuclear; Systemic Inflammatory Response Syndrome; Receptors, GABA
PubMed: 37905415
DOI: 10.1161/CIRCULATIONAHA.123.064734 -
Theranostics 2023: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis. However, how macrophage regulates fibroblast activation in...
: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis. However, how macrophage regulates fibroblast activation in the fibrotic kidney remains elusive. In this study, we show that macrophages promoted fibroblast activation by assembling a vitronectin (Vtn)-enriched, extracellular microenvironment. : We prepared decellularized kidney tissue scaffold (KTS) from normal and fibrotic kidney after unilateral ischemia-reperfusion injury (UIRI) and carried out an unbiased quantitative proteomics analysis. NRK-49F cells were seeded on macrophage-derived extracellular matrix (ECM) scaffold. Genetic Vtn knockout (Vtn-/-) mice and chronic kidney disease (CKD) model with overexpression of Vtn were used to corroborate a role of Vtn/integrin αvβ5/Src in kidney fibrosis. : Vtn was identified as one of the most upregulated proteins in the decellularized kidney tissue scaffold from fibrotic kidney by mass spectrometry. Furthermore, Vtn was upregulated in the kidney of mouse models of CKD and primarily expressed and secreted by activated macrophages. Urinary Vtn levels were elevated in CKD patients and inversely correlated with kidney function. Genetic ablation or knockdown of Vtn protected mice from developing kidney fibrosis after injury. Conversely, overexpression of Vtn exacerbated renal fibrotic lesions and aggravated renal insufficiency. We found that macrophage-derived, Vtn-enriched extracellular matrix scaffold promoted fibroblast activation and proliferation. In vitro, Vtn triggered fibroblast activation by stimulating integrin αvβ5 and Src kinase signaling. Either blockade of αvβ5 with neutralizing antibody or pharmacological inhibition of Src by Saracatinib abolished Vtn-induced fibroblast activation. Moreover, Saracatinib dose-dependently ameliorated Vtn-induced kidney fibrosis in vivo. These results demonstrate that macrophage induces fibroblast activation by assembling a Vtn-enriched extracellular microenvironment, which triggers integrin αvβ5 and Src kinase signaling. : Our findings uncover a novel mechanism by which macrophages contribute to kidney fibrosis via assembling a Vtn-enriched extracellular niche and suggest that disrupting fibrogenic microenvironment could be a therapeutic strategy for fibrotic CKD.
Topics: Mice; Animals; Vitronectin; Kidney; Renal Insufficiency, Chronic; src-Family Kinases; Macrophages; Fibroblasts; Fibrosis
PubMed: 37441594
DOI: 10.7150/thno.85250 -
Cancer Cell Oct 2023Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to...
Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683 T cells with response.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; CD8-Positive T-Lymphocytes; Lymphoma, Large B-Cell, Diffuse; Gene Expression Regulation; Immunotherapy
PubMed: 37738974
DOI: 10.1016/j.ccell.2023.08.013 -
Scientific Data Dec 2023The UCLA Cosmochemistry Database was initiated as part of a data-rescue and -storage project aimed at archiving a variety of cosmochemical data acquired at University of...
The UCLA Cosmochemistry Database was initiated as part of a data-rescue and -storage project aimed at archiving a variety of cosmochemical data acquired at University of California, Los Angeles (UCLA). The data collection includes elemental compositions of extraterrestrial materials analyzed by UCLA cosmochemists over the last five decades. The analytical techniques include atomic absorption spectrometry (AAS) and neutron activation analysis (NAA) at UCLA. The data collection is stored on the Astromaterials Data System (Astromat). We provide both interactive tables and downloadable datasheets for users to access all data. The UCLA Cosmochemistry Database archives cosmochemical data that are essential tools for increasing our understanding of the nature and origin of extraterrestrial materials. Future studies can reference the data collection in the examination, analysis, and classification of newly acquired extraterrestrial samples.
PubMed: 38062064
DOI: 10.1038/s41597-023-02807-7 -
The Journal of Clinical Investigation Nov 2023Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights...
Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.
Topics: Adult; Humans; Child; Arthritis, Juvenile; Biomarkers; Lung Diseases; Interferons; Genomics
PubMed: 37733441
DOI: 10.1172/JCI166741 -
Cardiovascular Research Oct 2023Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at...
AIMS
Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection.
METHODS AND RESULTS
In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group.
CONCLUSIONS
Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.
PubMed: 37517007
DOI: 10.1093/cvr/cvad114 -
Surgical Neurology International 2023
PubMed: 37680927
DOI: 10.25259/SNI_626_2023 -
Scientific Reports Nov 2023Bronchiolitis obliterans (BO) is a chronic airway disease that was often indicated by the pathological presentation of narrowed and irreversible airways. However, the...
Bronchiolitis obliterans (BO) is a chronic airway disease that was often indicated by the pathological presentation of narrowed and irreversible airways. However, the molecular mechanisms of BO pathogenesis remain unknown. Although neutrophil extracellular traps (NETs) can contribute to inflammatory disorders, their involvement in BO is unclear. This study aims to identify potential signaling pathways in BO by exploring the correlations between NETs and BO. GSE52761 and GSE137169 datasets were downloaded from gene expression omnibus (GEO) database. A series of bioinformatics analyses such as differential expression analysis, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were performed on GSE52761 and GSE137169 datasets to identify BO potential signaling pathways. Two different types of BO mouse models were constructed to verify NETs involvements in BO. Additional experiments and bioinformatics analysis using human small airway epithelial cells (SAECs) were also performed to further elucidate differential genes enrichment with their respective signaling pathways in BO. Our study identified 115 differentially expressed genes (DEGs) that were found up-regulated in BO. Pathway enrichment analysis revealed that these genes were primarily involved in inflammatory signaling processes. Besides, we found that neutrophil extracellular traps (NETs) were formed and activated during BO. Our western blot analysis on lung tissue from BO mice further confirmed NETs activation in BO, where neutrophil elastase (NE) and myeloperoxidase (MPO) expression were found significantly elevated. Transcriptomic and bioinformatics analysis of NETs treated-SAECs also revealed that NETs-DEGs were primarily associated through inflammatory and epithelial-to-mesenchymal transition (EMT) -related pathways. Our study provides novel clues towards the understanding of BO pathogenesis, in which NETs contribute to BO pathogenesis through the activation of inflammatory and EMT associated pathways. The completion of our study will provide the basis for potential novel therapeutic targets in BO treatment.
Topics: Humans; Mice; Animals; Extracellular Traps; Gene Expression Profiling; Transcriptome; Bronchiolitis Obliterans; Inflammation; Epithelial Cells; Computational Biology
PubMed: 37932341
DOI: 10.1038/s41598-023-45617-y -
IEEE Transactions on Neural Networks... May 2024In this article, we propose a generalization of the batch normalization (BN) algorithm, diminishing BN (DBN), where we update the BN parameters in a diminishing moving...
In this article, we propose a generalization of the batch normalization (BN) algorithm, diminishing BN (DBN), where we update the BN parameters in a diminishing moving average way. BN is very effective in accelerating the convergence of a neural network training phase that it has become a common practice. Our proposed DBN algorithm retains the overall structure of the original BN algorithm while introducing a weighted averaging update to some trainable parameters. We provide an analysis of the convergence of the DBN algorithm that converges to a stationary point with respect to the trainable parameters. Our analysis can be easily generalized to the original BN algorithm by setting some parameters to constant. To the best of our knowledge, this analysis is the first of its kind for convergence with BN. We analyze a two-layer model with arbitrary activation functions. Common activation functions, such as ReLU and any smooth activation functions, meet our assumptions. In the numerical experiments, we test the proposed algorithm on complex modern CNN models with stochastic gradients (SGs) and ReLU activation on regression, classification, and image reconstruction tasks. We observe that DBN outperforms the original BN algorithm and benchmark layer normalization (LN) on the MNIST, NI, CIFAR-10, CIFAR-100, and Caltech-UCSD Birds-200-2011 datasets with modern complex CNN models such as Resnet-18 and typical FNN models.
PubMed: 36260586
DOI: 10.1109/TNNLS.2022.3210840 -
Arthritis & Rheumatology (Hoboken, N.J.) Sep 2023Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small-molecule...
OBJECTIVE
Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small-molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD.
METHODS
We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition.
RESULTS
Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up-regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis.
CONCLUSION
We highlight key biologic effects of apremilast on neutrophils in BD.
Topics: Humans; Behcet Syndrome; Cyclic Nucleotide Phosphodiesterases, Type 4; Neutrophil Activation; Reactive Oxygen Species
PubMed: 36862398
DOI: 10.1002/art.42486