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In this issue, Su et al. report combined methylome and transcriptome analysis of cancer-associated fibroblasts (CAFs) compared with normal fibroblasts (NFs) from patients with non–small-cell lung cancer. They identify a DNA methylation signature in CAFs that correlates with survival in multiple patient cohorts. The cover art depicts the methylome (yellow-blue in nuclei) and transcriptome (red-blue in cytoplasm) landscapes of CAFs and NFs. Image credit: Huei-Wen Chen.
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Multisystem Inflammatory Syndrome in Children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here we utilized proteomics, RNA sequencing, autoantibody arrays and B-cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.
Rebecca A. Porritt, Aleksandra Binek, Lisa Paschold, Magali Noval Rivas, Angela Mc Ardle, Lael M. Yonker, Galit Alter, Harsha K. Chandnani, Merrick Lopez, Alessio Fasano, Jennifer E. Van Eyk, Mascha Binder, Moshe Arditi
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-derived platelet-derived growth factor (PDGF)-BB as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Mononuclear RANK+TRAP+ preosteoclasts in bone/bone marrow secrete excessive amount of PDGF-BB in aged mice and HFD mice. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3 times the serum PDGF-BB concentration of controls and developed simultaneous bone loss and arterial stiffening at young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration. Whereas wild-type mice fed HFD had augmented arterial stiffness, this effect was attenuated in conditional knockout mice. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.
Lakshmi Santhanam, Guanqiao Liu, Sandeep Jandu, Weiping Su, Bulouere P. Wodu, William Savage, Alan Poe, Xiaonan Liu, Lacy M. Alexander, Xu Cao, Mei Wan
There is an urgent need to identify cellular/molecular mechanisms responsible for severe COVID-19 progressing to mortality. We initially performed untargeted/targeted lipidomics and focused biochemistry on 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in severe COVID-19 patients. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 Group IIA (sPLA2-IIA), with a median value 9.6-fold higher than mild patients and 5.0-fold higher than severe COVID-19 survivors. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in stratifying patients that succumbed to COVID-19. Random forest analysis and LASSO-based regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than either alone. An independent cohort (n=154) confirmed higher plasma sPLA2-IIA levels in deceased patients vs. severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying mild, severe, and deceased COVID-19 patients. With clinically tested inhibitors available, this study supports sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
Justin M. Snider, Jeehyun Karen You, Xia Wang, Ashley J. Snider, Brian Hallmark, Manja M. Zec, Michael C. Seeds, Susan Sergeant, Laurel Johnstone, Qiuming Wang, Ryan Sprissler, Tara F. Carr, Karen Lutrick, Sairam Parthasarathy, Christian Bime, Hao H. Zhang, Chiara Luberto, Richard R. Kew, Yusuf A. Hannun, Stefano Guerra, Charles E. McCall, Guang Yao, Maurizio Del Poeta, Floyd H. Chilton
Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here we identify a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaces normal airspaces in a mouse model of progressive post-viral lung disease due to Sendai virus. Single-cell and lineage-tracing technologies identify a distinct subset of basal epithelial stem cells (basal-ESCs) that extend into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset is selectively expanded by crossing a cell growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that is independent of IL-33-receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupts homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuates post-viral disease in the lung based on down-regulation of remodeling and inflammation. We thereby identify a basal-ESC strategy to deploy innate-immune machinery that appears to overshoot the primordial goal of self-defense. The findings reveal new targets to stratify and correct chronic and often deadly post-viral disease.
Kangyun Wu, Kenji Kamimoto, Yong Zhang, Kuangying Yang, Shamus P. Keeler, Benjamin J. Gerovac, Eugene V. Agapov, Stephen P. Austin, Jennifer Yantis, Kelly A. Gissy, Derek E. Byers, Jennifer Alexander-Brett, Christy M. Hoffmann, Matthew Wallace, Michael E. Hughes, Erika C. Crouch, Samantha A. Morris, Michael J. Holtzman
BACKGROUND. The loss of insulin-like growth factor-1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of non-melanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin which upregulates dermal IGF-1 levels can prevent the occurrence of actinic keratosis (AK) and NMSC. METHODS. A human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human subjects aged ≥65. Finally, 48 subjects aged 60 and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion. RESULTS. Xenografting studies revealed chronic UVB treatment with a topical IGF-1R inhibitor resulted in a pro-carcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least two years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSC in the treated (24) versus untreated (2) arms. INTERPRETATION. The elimination of senescent fibroblasts via FLR reduced the pro-carcinogenic UVB response of aged skin. Thus, wounding therapies are potentially effective prophylaxis for managing high-risk populations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03906253. FUNDING. National Institutes of Health, Veterans Administration.
Dan F. Spandau, Roy Chen, Jeffrey J. Wargo, Craig A. Rohan, David Southern, Angela Zhang, Mathew Loesch, Jonathan Weyerbacher, Sunil S. Tholpady, Davina Anne Lewis, Matthew Kuhar, Kenneth Y. Tsai, Amber J. Castellanos, Michael G. Kemp, Michael Markey, Elizabeth Cates, Amy R. Williams, Christina Knisely, Sabina Bashir, Ryan Gabbard, Robert Hoopes, Jeffrey B. Travers
JCI This Month is a digest of the research, reviews, and other features published each month.
This collection of reviews focuses on the gut-brain axis, highlighting crosstalk between the gastrointestinal tract and the enteric and central nervous systems. While the enteric nervous system can exert independent control over the gut, multi-directional communication with the central nervous system, as well as intestinal epithelial, stromal, immune, and enteroendocrine cells can result in wide-ranging influences on health and disease. The gut microbiome and its metabolites add further complexity to this intricate interactive network. Reviews in this series take a critical approach to describing the role of gut-brain connections in conditions affecting both gut and brain, with the common goal of illuminating the importance of the central and enteric nervous system interface in disease pathogenesis and identifying nodes that offer therapeutic potential.