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Autumn G York, Mathias H Skadow, Rihao Qu, Joonseok Oh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Jason M Crawford, Stephen T Smale, Steven J Bensinger, Richard A Flavell
Unchecked chronic inflammation is the underlying cause of many diseases, ranging from inflammatory bowel disease to obesity and neurodegeneration. Given the deleterious nature of unregulated inflammation, it is not surprising that cells have acquired a diverse arsenal of tactics to limit inflammation. IL-10 is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types; however, the exact mechanism by which IL-10 signaling subdues inflammation remains unclear...
May 8, 2023: bioRxiv
#22
JOURNAL ARTICLE
Wenzhi Song, Gina M Sanchez, Daniel P Mayer, Holly N Blackburn, Irene Chernova, Richard A Flavell, Jason S Weinstein, Joe Craft
Tbet+CD11c+ B cells, also known as age-associated B cells (ABCs), are pivotal contributors to humoral immunity following infection and in autoimmunity, yet their in vivo generation is incompletely understood. We used a mouse model of systemic acute lymphocytic choriomeningitis virus infection to examine the developmental requirements of ABCs that emerged in the spleen and liver. IL-21 signaling through STAT3 was indispensable for ABC development. In contrast, IFN-γ signaling through STAT1 was required for B cell activation and proliferation...
May 3, 2023: Journal of Immunology
#23
Matthew Paul Reynolds, Gustavo Ariel Slafer, John Michael Foulkes, Simon Griffiths, Erik Harry Murchie, Elizabete Carmo-Silva, Senthold Asseng, Scott C Chapman, Mark Sawkins, Jeff Gwyn, Richard Bailey Flavell
No abstract text is available yet for this article.
August 2022: Nature food
#24
REVIEW
Matthew Paul Reynolds, Gustavo Ariel Slafer, John Michael Foulkes, Simon Griffiths, Erik Harry Murchie, Elizabete Carmo-Silva, Senthold Asseng, Scott C Chapman, Mark Sawkins, Jeff Gwyn, Richard Bailey Flavell
As crop yields are pushed closer to biophysical limits, achieving yield gains becomes increasingly challenging and will require more insight into deterministic pathways to yields. Here, we propose a wiring diagram as a platform to illustrate the interrelationships of the physiological traits that impact wheat yield potential and to serve as a decision support tool for crop scientists. The wiring diagram is based on the premise that crop yield is a function of photosynthesis (source), the investment of assimilates into reproductive organs (sinks) and the underlying processes that enable expression of both...
May 2022: Nature food
#25
JOURNAL ARTICLE
Hongdi Ma, Taidou Hu, Wanyin Tao, Jiyu Tong, Zili Han, Dietmar Herndler-Brandstetter, Zheng Wei, Ruize Liu, Tingyue Zhou, Qiuyuan Liu, Xuemei Xu, Kaiguang Zhang, Rongbin Zhou, Judy H Cho, Hua-Bing Li, Hailiang Huang, Richard A Flavell, Shu Zhu
Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus ("CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis") protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells...
April 13, 2023: Cell Research
#26
JOURNAL ARTICLE
Humanized MISTRG as a preclinical in vivo model to study human neutrophil-mediated immune processes.
Paula Martinez-Sanz, Adrien R G Laurent, Edith Slot, Mark Hoogenboezem, Nikolina Bąbała, Robin van Bruggen, Anthony Rongvaux, Richard A Flavell, Godelieve A M Tytgat, Katka Franke, Hanke L Matlung, Taco W Kuijpers, Derk Amsen, Julien J Karrich
INTRODUCTION: MISTRG mice have been genetically modified to allow development of a human myeloid compartment from engrafted human CD34+ haemopoietic stem cells, making them particularly suited to study the human innate immune system in vivo . Here, we characterized the human neutrophil population in these mice to establish a model that can be used to study the biology and contribution in immune processes of these cells in vivo . METHODS AND RESULTS: We could isolate human bone marrow neutrophils from humanized MISTRG mice and confirmed that all neutrophil maturation stages from promyelocytes (CD11b-CD16-) to end-stage segmented cells (CD11b+CD16+) were present...
2023: Frontiers in Immunology
#27
JOURNAL ARTICLE
Danping Zheng, Gayatree Mohapatra, Lara Kern, Yiming He, Merav D Shmueli, Rafael Valdés-Mas, Aleksandra A Kolodziejczyk, Tomasz Próchnicki, Matilde B Vasconcelos, Lena Schorr, Franziska Hertel, Ye Seul Lee, Miguel Camacho Rufino, Emmanuelle Ceddaha, Sandy Shimshy, Ryan James Hodgetts, Mally Dori-Bachash, Christian Kleimeyer, Kim Goldenberg, Melina Heinemann, Noa Stettner, Alon Harmelin, Hagit Shapiro, Jens Puschhof, Minhu Chen, Richard A Flavell, Eicke Latz, Yifat Merbl, Suhaib K Abdeen, Eran Elinav
Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1β and interleukin-18 secretion...
April 2023: Nature Immunology
#28
JOURNAL ARTICLE
James A Pearson, Jian Peng, Juan Huang, Xiaoqing Yu, Ningwen Tai, Youjia Hu, Sha Sha, Richard A Flavell, Hongyu Zhao, F Susan Wong, Li Wen
INTRODUCTION: Gut microbiota have been linked to modulating susceptibility to Type 1 diabetes; however, there are many ways in which the microbiota interact with host cells, including through microbial ligand binding to intracellular inflammasomes (large multi-subunit proteins) to initiate immune responses. NLRP6, a microbe-recognizing inflammasome protein, is highly expressed by intestinal epithelial cells and can alter susceptibility to cancer, obesity and Crohn's disease; however, the role of NLRP6 in modulating susceptibility to autoimmune diabetes, was previously unknown...
2023: Frontiers in Immunology
#29
JOURNAL ARTICLE
Carl-Philipp Hackstein, Jasper Spitzer, Konstantinos Symeonidis, Helena Horvatic, Tanja Bedke, Babett Steglich, Sabine Klein, Lisa M Assmus, Alexandru Odainic, Jennifer Szlapa, Nina Kessler, Marc Beyer, Ricarda Schmithausen, Eicke Latz, Richard A Flavell, Natalio Garbi, Christian Kurts, Beate M Kümmerer, Jonel Trebicka, Axel Roers, Samuel Huber, Susanne V Schmidt, Percy A Knolle, Zeinab Abdullah
BACKGROUND & AIMS: Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD. METHODS: We combined bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) models of liver injury with vaccination or lymphocytic choriomeningitis virus infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox ), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox ) or IL-10R in T cells (CD4-DN IL-10R)...
July 2023: Journal of Hepatology
#30
JOURNAL ARTICLE
Guus H van Muijlwijk, Tyler A Rice, Richard A Flavell, Noah W Palm, Marcel R de Zoete
As part of a culturomics study to identify bacterial species associated with inflammatory bowel disease, a large collection of bacteria was isolated from patients with ulcerative colitis. Two of these isolates were tentatively identified as members of the family Erysipelotrichaceae . Following phylogenetic analysis based on 16S rRNA gene sequence and genome sequences, both strain 128T and 539T were found to be most closely related to Allobaculum stercoricanis , with G+C contents of 48.6 and 50.5 mol%, respectively, and the genome sizes of 2 864 314 and 2 580 362 base pairs, respectively...
February 2023: International Journal of Systematic and Evolutionary Microbiology
#31
JOURNAL ARTICLE
Xingxing Ren, Decai Wang, Guorong Zhang, Tingyue Zhou, Zheng Wei, Yi Yang, Yunjiang Zheng, Xuqiu Lei, Wanyin Tao, Anmin Wang, Mingsong Li, Richard A Flavell, Shu Zhu
RNA helicase DHX9 has been extensively characterized as a transcriptional regulator, which is consistent with its mostly nucleic localization. It is also involved in recognizing RNA viruses in the cytoplasm. However, there is no in vivo data to support the antiviral role of DHX9; meanwhile, as a nuclear protein, if and how nucleic DHX9 promotes antiviral immunity remains largely unknown. Here, we generated myeloid-specific and hepatocyte-specific DHX9 knockout mice and confirmed that DHX9 is crucial for host resistance to RNA virus infections in vivo...
February 3, 2023: Science Advances
#32
JOURNAL ARTICLE
Mitchell Buster, Steven Simpfendorfer, Christopher Guppy, Mike Sissons, Richard J Flavel
The cereal disease Fusarium crown rot (FCR), caused by the fungal pathogen Fusarium pseudograminearum ( Fp ), is a major constraint to cereal production worldwide. Nitrogen (N) fertilizer is estimated to be approximately 30% of the input costs for grain growers in Australia and is the primary driver of yield and grain protein levels. When targeting high yield and protein, generous nitrogen fertilizer applications are thought to result in large biomass production, which exacerbates FCR severity, reducing grain yield and quality...
January 24, 2023: Plants (Basel, Switzerland)
#33
JOURNAL ARTICLE
Daria Briukhovetska, Javier Suarez-Gosalvez, Cornelia Voigt, Anamarija Markota, Anastasios D Giannou, Maryam Schübel, Jakob Jobst, Tao Zhang, Janina Dörr, Florian Märkl, Lina Majed, Philipp Jie Müller, Peter May, Adrian Gottschlich, Nicholas Tokarew, Jöran Lücke, Arman Oner, Melanie Schwerdtfeger, David Andreu-Sanz, Ruth Grünmeier, Matthias Seifert, Stefanos Michaelides, Michael Hristov, Lars M König, Bruno Loureiro Cadilha, Oleg Mikhaylov, Hans-Joachim Anders, Simon Rothenfusser, Richard A Flavell, Daniela Cerezo-Wallis, Cristina Tejedo, María S Soengas, Tobias Bald, Samuel Huber, Stefan Endres, Sebastian Kobold
Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice...
January 10, 2023: Immunity
#34
JOURNAL ARTICLE
Anastasios D Giannou, Jan Kempski, Ahmad Mustafa Shiri, Jöran Lücke, Tao Zhang, Lilan Zhao, Dimitra E Zazara, Filippo Cortesi, Kristoffer Riecken, Maria Carolina Amezcua Vesely, Jun Siong Low, Hao Xu, Eleanna Kaffe, Laura Garcia-Perez, Theodora Agalioti, Yoshito Yamada, Wolfgang Jungraithmayr, Ehud Zigmond, Karl-Frederick Karstens, Babett Steglich, Jonas Wagner, Leonie Konczalla, Antonella Carambia, Kornelius Schulze, Johann von Felden, Peter May, Daria Briukhovetska, Tanja Bedke, Leonie Brockmann, Sarah Starzonek, Tobias Lange, Claudia Koch, Sabine Riethdorf, Penelope Pelczar, Marius Böttcher, Morsal Sabihi, Francis J Huber, Matthias Reeh, Julia Kristin Grass, Ramez Wahib, Hannes Seese, Björn-Ole Stüben, Mohammad Fard-Aghaie, Anna Duprée, Pasquale Scognamiglio, Gabriel Plitzko, Jan Meiners, Shiwa Soukou, Agnes Wittek, Caroline Manthey, Ioannis C Maroulis, Petra C Arck, Daniel Perez, Bin Gao, Sotirios G Zarogiannis, Till Strowig, Renata Pasqualini, Wadih Arap, Javier Suárez Gosálvez, Sebastian Kobold, Immo Prinz, Andreas H Guse, Michael Tachezy, Tarik Ghadban, Asmus Heumann, Jun Li, Nathaniel Melling, Oliver Mann, Jakob R Izbicki, Klaus Pantel, Udo Schumacher, Ansgar W Lohse, Richard A Flavell, Nicola Gagliani, Samuel Huber
During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis...
January 10, 2023: Immunity
#35
JOURNAL ARTICLE
Robert Nechanitzky, Duygu Nechanitzky, Parameswaran Ramachandran, Gordon S Duncan, Chunxing Zheng, Christoph Göbl, Kyle T Gill, Jillian Haight, Andrew C Wakeham, Bryan E Snow, Vivian Bradaschia-Correa, Milan Ganguly, Zhibin Lu, Mary E Saunders, Richard A Flavell, Tak W Mak
Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS) in which Th17 cells have a crucial but unclear function. Here we show that choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), is a critical driver of pathogenicity in EAE. Mice with ChAT-deficient Th17 cells resist disease progression and show reduced brain-infiltrating immune cells. ChAT expression in Th17 cells is linked to strong TCR signaling, expression of the transcription factor Bhlhe40, and increased Il2, Il17, Il22, and Il23r mRNA levels...
December 17, 2022: Cell Death and Differentiation
#36
JOURNAL ARTICLE
Ian D Odell, Holly Steach, Stephen B Gauld, Lauren Reinke-Breen, Jozsef Karman, Tracy L Carr, Joseph B Wetter, Lucy Phillips, Monique Hinchcliff, Richard A Flavell
Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs...
December 16, 2022: Science Immunology
#37
JOURNAL ARTICLE
Xian Zhang, Songyuan Luo, Minjie Wang, Qiongqiong Cao, Zhixin Zhang, Qin Huang, Jie Li, Zhiyong Deng, Tianxiao Liu, Cong-Lin Liu, Mathilde Meppen, Amelie Vromman, Richard A Flavell, Gökhan S Hotamışlıgil, Jian Liu, Peter Libby, Zhangsuo Liu, Guo-Ping Shi
White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT...
December 8, 2022: Nature Communications
#38
JOURNAL ARTICLE
Richard B Flavell
The low rates of yield gain in wheat breeding programs create an ominous situation for the world. Amongst the reasons for this low rate are issues manifested in spike development that result in too few spikelets, fertile florets and therefore grains being produced. Phases in spike development are particularly sensitive to stresses of various kinds and origins and these are partly responsible for the deficiencies in grain production and slow rates of gain in yield. The diversity of developmental processes, stresses and the large numbers of genes involved make it particularly difficult to prioritise approaches in breeding programs without an overarching, mechanistic framework...
December 7, 2022: Journal of Experimental Botany
#39
JOURNAL ARTICLE
Jérémie Prévost, Sai Priya Anand, Jyothi Krishnaswamy Rajashekar, Li Zhu, Jonathan Richard, Guillaume Goyette, Halima Medjahed, Gabrielle Gendron-Lepage, Hung-Ching Chen, Yaozong Chen, Joshua A Horwitz, Michael W Grunst, Susan Zolla-Pazner, Barton F Haynes, Dennis R Burton, Richard A Flavell, Frank Kirchhoff, Beatrice H Hahn, Amos B Smith, Marzena Pazgier, Michel C Nussenzweig, Priti Kumar, Andrés Finzi
Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity...
November 8, 2022: Cell Reports
#40
JOURNAL ARTICLE
Alexandra Gatsios, Chung Sub Kim, Autumn G York, Richard A Flavell, Jason M Crawford
Escherichia coli isolates commonly inhabit the human microbiota, yet the majority of E. coli 's small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from "abortive" tRNA synthetase reactions in pathogenic, commensal, and probiotic E. coli isolates. In this study, we explored the "missing" tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress...
November 8, 2022: Journal of Natural Products
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