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Peer review is the driving force of journal development, and reviewers are gatekeepers who ensure that C maintains its standards for the high quality of its published papers. Thanks to the cooperation of our reviewers, in 2020, the median time to first decision was 13 days and the median time to publication was 35 days. The editors would like to express their sincere gratitude to the following reviewers for their precious time and dedication, regardless of whether the papers were finally published: A., Plyushch Lee, Ilkeun Aga, Omer Lee, Wonhee Alberto, Vertova Lee, Young-Chul Alvarez-Merino, Miguel Angel Levesque, Dominique Álvaro, Caballero Lim, Dong Chan Andreoli, Enrico Lissorgues, Gaelle Ang, Yee Sin Lloret, Fernando Arandiyan, Hamidreza Llosa Tanco, Margot A. Ariga, Katsuhiko Loescher, Henry Aschilean, Ioan Longhi, Mariangela Ashourirad, Babak Longo, Angela Ataide, Janaína Artem López-Lorente, Ángela Inmaculada Bajales, Noelia Lorandi, Francesca Bansode, Atul Lu, Jingyu Bao, Weizhai Majewski, Jacek A. Bao, Yi Malhotra, Deepika Bartoli, Mattia Marchese, Marco Bassano, Claudia Marino, Bruno Bechelany, Mikhael Martinelli, Michela Bellucci, Stefano Martínez-Periñán, Emiliano Benedic, Fabien Matanovic, Ivana Bermejo, M. Dolores Medyńska-Juraszek, Agnieszka Beszédes, Sándor Melin, Frederic Bimbela, Fernando Mena, Ismael F. Blacha-Grzechnik, Agata Meskinis, Sarunas Bouhamed, Ayda Morgan, David Burger, Michael C Moyseowicz, Adam Cabaj, Joanna Myongwon Lee, Lucia Calvo, Luisa Nair, Mahesh Camélia, Matei Ghimbeu Naito, Katsuyuki Cammarata, Antonio Nautiyal, Amit Cao, Jianyun Nemnes, George Alexandru Cazorla-Amorós, Diego Nie, Chuanxiong Cazzanelli, Massimo Nielsen, Vance Girard Cecilia, Hodur Nitsos, Christos K. Cecone, Claudio Ola, Oluwafunmilola Centeno, Miguel Angel Palella, Alessandra Ceran, Bartosz Palo, Emma Cesano, Federico Pant, Bishweshwar Chen, Houyang Pasinszki, Tibor Cheraghian, Goshtasp Pelicano, Christian Mark Chernozatonskii, Leonid A. Pereira, Adelino Cho, Jung Sang Polanski, Marek Chukov, Dilyus Politano, Grazia Giuseppina Ciszewski, Mateusz Popov, Maxim N. Czujko, Tomasz Radtke, Aleksandra Danso-Boateng, Eric Radulescu, Aurel Dato, Albert Rahimi, Mohammad Datta, Rahul Ray, Supriyo De Luca, Pierantonio Rebholz, Claus Deng, Renhua Regulska, Elzbieta Derry, Paul Reshetnyak, Victor Dettlaff, Anna Restivo, João Dhaliwal, Gurjot S. Richtera, Lukas Dimitratos, Nikolaos Robles, Eduardo Dzikuć, Maria Rogala, Andrzej Elmouwahidi, Abdelhakim Rovira, Pere Endrodi, Balazs Rozzi, Elena Fabisiak, Kazimierz Ruocco, Concetta Fedel, Mariangela Ruuskanen, Vesa Ficek, Mateusz Salahub, Dennis Florio, Ciro San Fabian, Emilio Flox, Cristina Scheibe, Błażej Friák, Martin Schuster, Bernhard Gadipelli, Srinivas Schweiss, Ruediger Gao, Zhe Semaltianos, Nikolaos G. Garbovskiy, Yuriy Serrano, Aida Gauden, Piotr Sharma, Shiv K. Gavrilov, Nemanja Sher, Farooq Gentile, Marialuisa Shinde, Surendra Krushna Ghosh, Subrata Shrestha, Lok Giuliano, Aristide Simonpietro, Agnello Glukhova, Olga E. Singh, Gurwinder Gnyba, Marcin Solano, Francisco Golub, Igor Song , Kenan Gorkunov, Maxim V. Speranza, Giorgio Goswami, Sumita Stoof, HTC Grekov, Denys Strąkowska, Anna Guerrero-Pérez, M. Olga Strozzi, Matteo Guzman, Marcelo Stylianakis, Minas Habuda-Stanic, Mirna Su, Chie-Shaan Hampton, Michael Sysoev, Vitalii I. Handoko, Albertus Szałowski, Karol Haniu, Hisao Szekely, Gyorgy Haque, Ariful Szybowicz, Miroslaw Harja, Maria Takada, Tomoya Harris, Peter Tang, Longteng Hayashi, Noriko Torres, Daniel Hayashi, Takuya Trefon-Radziejewska, Dominika Hernández Saz, Jesús Trindle, Carl Herranz, Maria Angeles Trinh, Minh Chien Hiete, Michael Trovarelli, Alessandro Hinman, Samuel Trusso Sfrazzetto, Giuseppe Hu, John Ullrich, Carsten Inaba, Masafumi Vacacelagomez, Cristianisaac Jan Laskowski, Łukasz Valero-Romero, María José Janas, Dawid Vicente, Yolanda Sánchez Jin, Kyoungsuk Voutsas, Epaminondas Kanda, Kazuhiro Wang, Fenjuan Kelarakis, Antonios Wang, Gang Kepinska, Marta Wang, Xianyou Kogan, Eugene Wei, Zhu Konyashin, Igor Wieczorek, Władysław G. Kopel, Pavel Wiśniewski, Marek Korznikova, Elena Włoch, Marcin Kothandaraman, Jotheeswari Xia, Guanglin Kraka, Elfi Xiao, Xin Kratochvilova, Irena Xin, Hai Krzywiecki, Maciej Xiong, Hui Kumar, Harish Xu, Tao Kumar, Vivek Yang, Euntae Kuś, Wacław Yang, Ju-chan Kusters, Ilja Yoshida, Kentaro La, Duc Duong Zaffora, Andrea Lamouroux, Emmanuel Zhang, Xiaoyan Lavagna, Luca Zhao, Xinxin (Cindy) Le Normand, Francois Zhu, Xiaolong LeBlanc, Roger M Zieliński, Andrzej C Editorial Office MDPI AG, St. Alban-Anlage 66, 4052 Basel, Switzerland

Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5 flox/flox (ALK5 ΔCD8 ) mice reject tumors in high proportions, dependent on CD8 + T cells. ALK5 ΔCD8 mice have more tumor-infiltrating effector CD8 + T cells, with more cytotoxic capacity. ALK5-deficient CD8 + T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5 ΔCD8 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8 + T cells, thereby limiting their trafficking into tumors. TGFβ has a role in cancer immunosuppression but the exact mechanisms haven’t been fully elucidated. Here, using mouse models deficient in TGFβ-signaling, the authors show that loss of ALK5 in CD8 + T cells enhances their tumour trafficking and cytotoxicity suggesting that ALK5 inhibitors may have clinical utility.

Located within the brain’s ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klotho flox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.

Extracellular DNA traps (ETs) represent an immune response by which cells release essential materials like chromatin and granular proteins. Previous studies have demonstrated that the transdifferentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. This study seeks to investigate the interaction between CD68 + VSMCs and the formation of ETs and highlight its function in atherosclerosis. Here we show that ETs are inhibited, and atherosclerotic plaque formation is alleviated in male Myh11 Cre Pad4 flox/flox mice undergoing an adeno-associated-virus-8 (AAV8) mediating overexpression of proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) injection and being challenged with a high-fat diet. Obvious ETs generated from CD68 + VSMCs are inhibited by Cl-amidine and DNase I in vitro. By utilizing VSMCs-lineage tracing technology and single-cell RNA sequencing (scRNA-seq), we demonstrate that the ETs from CD68 + VSMCs influence the progress of atherosclerosis by regulating the direction of VSMCs’ transdifferentiation through STING-SOCS1 or TLR4 signaling pathway. Vascular smooth muscle cells (VSMCs) are known for their fate plasticity in atherosclerosis plaque progression. Here, Zhai et al. show that extracellular traps generated from CD68  + VSMCs adversely contribute to plaque progression and highlight their unexpected role in plaque stability by regulating the direction of VSMC trans-differentiation.

Immune response plays a crucial role in post-myocardial infarction (MI) myocardial remodeling. Neogenin (Neo1), a multifunctional transmembrane receptor, plays a critical role in the immune response; however, whether Neo1 participates in pathological myocardial remodeling after MI is unclear. Our study found that Neo1 expression changed significantly after MI in vivo and after LPS + IFN-γ stimulation in bone marrow-derived macrophages (BMDMs) in vitro. Neo1 functional deficiency (using a neutralizing antibody) and macrophage-specific Neo1 deficiency (induced by Neo1 flox/flox ;Cx3cr1 cre mice) increased infarction size, enhanced cardiac fibrosis and cardiomyocyte apoptosis, and exacerbated left ventricular dysfunction post-MI in mice. Mechanistically, Neo1 deficiency promoted macrophage infiltration into the ischemic myocardium and transformation to a proinflammatory phenotype, subsequently exacerbating the inflammatory response and impairing inflammation resolution post-MI. Neo1 deficiency regulated macrophage phenotype and function, possibly through the JAK1-STAT1 pathway, as confirmed in BMDMs in vitro. Blocking the JAK1-STAT1 pathway with fludarabine phosphate abolished the impact of Neo1 on macrophage phenotype and function, inflammatory response, inflammation resolution, cardiomyocyte apoptosis, cardiac fibrosis, infarction size and cardiac function. In conclusion, Neo1 deficiency aggravates inflammation and left ventricular remodeling post-MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway. These findings highlight the anti-inflammatory potential of Neo1, offering new perspectives for therapeutic targets in MI treatment. Graphical abstract Neo1 deficiency aggravated inflammation and left ventricular remodeling after MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway.

Mutations in TGFBR2, a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models, Tgfbr2 inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by TGFBR2 inactivation following disruption of the Wnt-β-catenin pathway. We previously described CDX2P-G19Cre;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice, with simultaneous loss of Apc and Tgfbr2. These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis. Our results showed that the expression of the murine homolog of GSDMC was significantly upregulated by 9.25-fold in tumors of CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice compared with those of CDX2P-G19Cre;Apcflox/flox mice. We then investigated the role of GSDMC in regulating CRC tumorigenesis. The silencing of GSDMC led to a significant reduction in the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GSDMC enhanced cell proliferation. These results suggested that GSDMC functioned as an oncogene, promoting cell proliferation in colorectal carcinogenesis. In conclusion, combined inactivation of both Apc and Tgfbr2 in the colon epithelium of a CRC mouse model promoted development of adenocarcinoma in the proximal colon. Moreover, GSDMC was upregulated by TGFBR2 mutation in CRC and promoted tumor cell proliferation in CRC carcinogenesis, suggesting that GSDMC may be a promising therapeutic target.

SND1 and MTDH are known to promote cancer and therapy resistance, but their mechanisms and interactions with other oncogenes remain unclear. Here, we show that oncoprotein ERG interacts with SND1/MTDH complex through SND1’s Tudor domain. ERG , an ETS-domain transcription factor, is overexpressed in many prostate cancers. Knocking down SND1 in human prostate epithelial cells, especially those overexpressing ERG , negatively impacts cell proliferation. Transcriptional analysis shows substantial overlap in genes regulated by ERG and SND1 . Mechanistically, we show that ERG promotes nuclear localization of SND1/MTDH. Forced nuclear localization of SND1 prominently increases its growth promoting function irrespective of ERG expression. In mice, prostate-specific Snd1 deletion reduces cancer growth and tumor burden in a prostate cancer model ( PB-Cre/Pten flox/flox / ERG mice), Moreover, we find a significant overlap between prostate transcriptional signatures of ERG and SND1. These findings highlight SND1’s crucial role in prostate tumorigenesis, suggesting SND1 as a potential therapeutic target in prostate cancer. The ETS family transcription factor ERG is frequently overexpressed in prostate cancer and known to have a role in carcinogenesis, however, the underlying mechanism is less understood. Here, the authors report an interaction between ERG and SND1 as necessary for ERG-driven prostate cancer initiation using preclinical models.

Treg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3 + ST2 + intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3 + Treg cells in Foxp3 Cre-YFP Setd2   flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1 ) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2. Treg cells can be functionally altered by epigenetic modulators. Here the authors show that the histone H3K36 methyltransferase Setd2 is important for the survival of Treg cells and for the regulation of IL-33 mediated Th2 responses in mice and SETD2 expression is increased in Treg cells from human colorectal cancer tissue.

Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.

Brown adipose tissue (BAT) thermogenesis is pivotal for maintaining body temperature and energy balance. Mitochondrial morphology is dynamically controlled by a balance between fusion and fission, which is crucial for cell differentiation, response to metabolic insults, and heat production. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. This study investigates the role of Drp1 in BAT development and thermogenesis by generating Drp1-deficient mice. These mice were created by crossing Drp1 floxed mice with fatty acid-binding protein 4-Cre ( aP2 -Cre) transgenic mice, resulting in aP2 -Cre +/- Drp1 flox/flox ( aP2-Drp1 f/f ) mice. The aP2-Drp1 f/f mice exhibited severe BAT and brain hypoplasia, with the majority dying within 48 hours postnatally, highlighting Drp1’s crucial role in neonatal survival. Impaired thermogenic responses were observed in aP2-Drp1 f/f mice, characterized by significantly decreased expression of thermogenic and lipogenic genes in BAT. Ultrastructural analysis revealed disrupted mitochondrial morphology and reduced lipid droplet content in BAT. The few surviving adult aP2-Drp1 f/f mice also showed impaired BAT and brain development, along with BAT thermogenesis dysfunction during cold exposure. Our findings underscore the essential role of Drp1-mediated mitochondrial fission in BAT thermogenesis and neonatal survival, providing insights into potential therapeutic approaches for metabolic disorders.