Fowler et al. report that neutrophils act as oxygen sinks and modify CD8+ T cell behavior in the inflamed skin. The cover art shows staining of neutrophils (Ly6G, pink) and hypoxic regions (pimonidazole, green) in murine skin following Leishmania infection.
Notch signaling can have either an oncogenic or tumor suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine prostate cancer where it functions as a tumor suppressor. Activation of Notch in neuroendocrine and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion towards a more indolent non-neuroendocrine state with glandular features and expression of luminal lineage markers. This was accompanied by up-regulation of MHC and type I interferon and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of neuroendocrine differentiation in advanced prostate cancer and provides insights into how Notch signaling influences lineage plasticity and the tumor microenvironment.
Sheng-Yu Ku, Yanqing Wang, Maria Mica Garcia, Yasutaka Yamada, Kei Mizuno, Mark D. Long, Spencer Rosario, Meenalakshmi Chinnam, Majd Al Assaad, Loredana Puca, Min Jin Kim, Martin K. Bakht, Varadha Balaji Venkadakrishnan, Brian D. Robinson, Andrés M. Acosta, Kristine M. Wadosky, Juan Miguel Mosquera, David W. Goodrich, Himisha Beltran
Intestinal fibrosis, a severe complication of Crohn’s disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective anti-fibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-seq) of fibrotic and non-fibrotic ileal tissues from CD patients with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP+ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single cell transcriptomic profiling of chronic Dextran Sulfate Sodium Salt (DSS) murine colitis model revealed Cd81+Pi16– fibroblasts exhibited transcriptomic and functional similarities to human FAP+ fibroblasts. Consistently, FAP+ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP+ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9+ macrophages enriched in fibrotic tissues via IL-1β and TGF-β signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.
Yao Zhang, Jiaxin Wang, Hongxiang Sun, Zhenzhen Xun, Zirui He, Yizhou Zhao, Jingjing Qi, Sishen Sun, Qidi Yang, Yubei Gu, Ling Zhang, Chunhua Zhou, Youqiong Ye, Ningbo Wu, Duowu Zou, Bing Su
Neovascular age-related macular degeneration (nAMD) remains a major cause of visual impairment and puts considerable burden on patients and health care systems. L-DOPA-treated Parkinson Disease (PD) patients have been shown to be partially protected from nAMD, but the mechanism remains unknown. Using murine models, combining 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and laser-induced nAMD, standard PD treatment of L-DOPA/DOPA-decarboxylase inhibitor, or specific dopamine receptor inhibitors, we here demonstrate that L-DOPA treatment-induced increase of dopamine mediated dopamine receptor D2 (DRD2) signaling inhibits choroidal neovascularization independently of MPTP-associated nigrostriatal pathway lesion. Analyzing a retrospective cohort of more than two hundred thousand nAMD patients receiving anti-VEGF treatment from the French nationwide insurance database, we show that DRD2-agonist treated (PD) patients have a significantly delayed age of onset for nAMD (81.4 (±7.0) vs 79.4 (±8.1) years old, respectively, p<0.0001) and reduced need for anti-VEGF therapies (-0.6 injections per 100 mg/day daily dose of DRD2 agonists the second year of treatment), similar to the L-DOPA treatment. While providing a mechanistic explanation for an intriguing epidemiological observation, our findings suggest that systemic DRD2 agonists might constitute an adjuvant therapy to delay and reduce the need for anti-VEGF therapy in nAMD patients.
Thibaud Mathis, Florian Baudin, Anne-Sophie Mariet, Sébastien Augustin, Marion Bricout, Lauriane Przegralek, Christophe Roubeix, Éric Benzenine, Guillaume Blot, Caroline Nous, Laurent Kodjikian, Martine Mauget-Faÿsse, José-Alain Sahel, Robin Plevin, Christina Zeitz, Cécile Delarasse, Xavier Guillonneau, Catherine Creuzot-Garcher, Catherine Quantin, Stéphane Hunot, Florian Sennlaub
Vicente Quiroz, Laura Planas-Serra, Abigail Sveden, Amy Tam, Hyo M. Kim, Umar Zubair, Dario Resch, Afshin Saffari, Matt C. Danzi, Stephan Züchner, Maya Chopra, Luca Schierbaum, Aurora Pujol, Erik A. Eklund, Darius Ebrahimi-Fakhari
BACKGROUND. There is uncertainty around the timing of booster vaccination against COVID-19 in highly vaccinated populations during the present endemic phase of COVID-19. Studies focused on primary vaccination have previously suggested improved immunity after delaying immunisation. METHODS. We conducted a randomised controlled trial (Nov 2022 – Aug 2023) and assigned 52 fully vaccinated adults to an immediate or a 3-month delayed bivalent Spikevax mRNA booster vaccine. Follow-up visits were completed for 48 participants (n = 24 per arm), with saliva and plasma samples collected following each visit. RESULTS. The rise in neutralising antibody responses to ancestral and Omicron strains were almost identical between the immediate and delayed vaccination arms. Analyses of plasma and salivary antibody responses (IgG, IgA), plasma antibody-dependent phagocytic activity, and the decay kinetics of antibody responses were similar between the 2 arms. Symptomatic and asymptomatic SARS-CoV-2 infection occurred in 49% (21/49) participants over the median 11.5 months of follow up and were also similar between the 2 arms. CONCLUSIONS. Our data suggests no benefit from delaying COVID-19 mRNA booster vaccination in pre-immune populations during the present endemic phase of COVID-19 TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry number 12622000411741. FUNDING. National Health and Medical Research Council, Australia, Program Grant App1149990 and Medical Research Future Fund App2005544.
Wen Shi Lee, Jennifer Audsley, Mai-Chi Trieu, Arnold Reynaldi, L. Carissa Aurelia, Palak H. Mehta, Joanne Patterson, Helen E. Kent, Julie Nguyen, Thakshila Amarasena, Robyn Esterbauer, Ebene R. Haycroft, Pradhipa Ramanathan, Miles P. Davenport, Timothy E. Schlub, Joseph Sasadeusz, Adam K. Wheatley, Amy W. Chung, Jennifer A. Juno, Kevin J. Selva, Stephen J. Kent
JCI celebrates a century of publishing scientific discoveries with a special collection highlighting major innovations in medicine and key contributing mechanistic studies.
Vascular malformations in arteries, veins, and lymphatic vessels occur in a broad range of conditions that vary widely in severity and presentation. Leveraging the mechanisms specific to each type of malformation will be essential for optimizing disease management. This review series, developed with series editor Miikka Vikkula, will span hemangioma, hereditary hemorrhagic telangiectasia, lymphatic abnormalities, cerebral small vessel disease, capillary malformations, and more, with reviews contributed by leading experts in each condition.
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