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JOURNAL ARTICLE
Xingxing Ren, Qiuyuan Liu, Peirong Zhou, Tingyue Zhou, Decai Wang, Qiao Mei, Richard A Flavell, Zhanju Liu, Mingsong Li, Wen Pan, Shu Zhu
Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC ) exhibit an increased susceptibility to experimental colitis...
April 9, 2024: Nature Communications
#2
JOURNAL ARTICLE
Rihao Qu, Xiuyuan Cheng, Esen Sefik, Jay S Stanley Iii, Boris Landa, Francesco Strino, Sarah Platt, James Garritano, Ian D Odell, Ronald Coifman, Richard A Flavell, Peggy Myung, Yuval Kluger
Single-cell RNA sequencing has been widely used to investigate cell state transitions and gene dynamics of biological processes. Current strategies to infer the sequential dynamics of genes in a process typically rely on constructing cell pseudotime through cell trajectory inference. However, the presence of concurrent gene processes in the same group of cells and technical noise can obscure the true progression of the processes studied. To address this challenge, we present GeneTrajectory, an approach that identifies trajectories of genes rather than trajectories of cells...
April 5, 2024: Nature Biotechnology
#3
JOURNAL ARTICLE
Autumn G York, Mathias H Skadow, Joonseok Oh, Rihao Qu, Quan D Zhou, Wei-Yuan Hsieh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Stephen T Smale, Jason M Crawford, Steven J Bensinger, Richard A Flavell
Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1 . Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5 . Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency...
February 21, 2024: Nature
#4
JOURNAL ARTICLE
Ahmad Mustafa Shiri, Tao Zhang, Tanja Bedke, Dimitra E Zazara, Lilan Zhao, Jöran Lücke, Morsal Sabihi, Antonella Fazio, Siwen Zhang, Daniele V F Tauriello, Eduard Batlle, Babett Steglich, Jan Kempski, Theodora Agalioti, Mikołaj Nawrocki, Yang Xu, Kristoffer Riecken, Imke Liebold, Leonie Brockmann, Leonie Konczalla, Lidia Bosurgi, Baris Mercanoglu, Philipp Seeger, Natalie Küsters, Panagis M Lykoudis, Asmus Heumann, Petra C Arck, Boris Fehse, Philipp Busch, Rainer Grotelüschen, Oliver Mann, Jakob R Izbicki, Thilo Hackert, Richard A Flavell, Nicola Gagliani, Anastasios D Giannou, Samuel Huber
BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastasis is reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Here, we aimed to investigate the role of IL-10 in liver metastasis formation and decipher its therapeutic potential in affecting immunotherapy effectiveness. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively...
December 29, 2023: Journal of Hepatology
#5
JOURNAL ARTICLE
Tommaso Torcellan, Christin Friedrich, Rémi Doucet-Ladevèze, Thomas Ossner, Virgínia Visaconill Solé, Sofie Riedmann, Milas Ugur, Fabian Imdahl, Stephan P Rosshart, Sebastian J Arnold, Mercedes Gomez de Agüero, Nicola Gagliani, Richard A Flavell, Simone Backes, Wolfgang Kastenmüller, Georg Gasteiger
Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hi CD69hi trNK cells that share transcriptional similarity with CD56bright TCF1hi NK cells in human tissues...
January 9, 2024: Immunity
#6
JOURNAL ARTICLE
Berna Sozen, Richard A Flavell, Dudley W Lamming, Debra L Silver, Simona Parrinello, Cory Abate-Shen, Franziska Michor, Vijay G Sankaran
Researchers are leveraging what we have learned from model organisms to understand if the same principles arise in human physiology, development, and disease. In this collection of Voices, we asked researchers from different fields to discuss what tools and insights they are using to answer fundamental questions in human biology.
December 18, 2023: Developmental Cell
#7
Xuchen Zhang, Peiying Shan, Leo E Otterbein, Jawed Alam, Richard A Flavell, Roger J Davis, Augustine M K Choi, Patty J Lee
No abstract text is available yet for this article.
October 9, 2023: Journal of Biological Chemistry
#8
JOURNAL ARTICLE
Yimeng Gao, Joshua T Zimmer, Radovan Vasic, Chengyang Liu, Rana Gbyli, Shu-Jian Zheng, Amisha Patel, Wei Liu, Zhihong Qi, Yaping Li, Raman Nelakanti, Yuanbin Song, Giulia Biancon, Andrew Z Xiao, Sarah Slavoff, Richard G Kibbey, Richard A Flavell, Matthew D Simon, Toma Tebaldi, Hua-Bing Li, Stephanie Halene
N6 -methyladenosine (m6 A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6 A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6 A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels...
September 23, 2023: Cell Reports
#9
REVIEW
Eleanna Kaffe, Annamaria Tisi, Christiana Magkrioti, Vassilis Aidinis, Wajahat Z Mehal, Richard A Flavell, Mauro Maccarrone
Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases...
January 2024: Journal of Hepatology
#10
JOURNAL ARTICLE
Ian D Odell, Kriti Agrawal, Esen Sefik, Anahi V Odell, Elizabeth Caves, Nancy C Kirkiles-Smith, Valerie Horsley, Monique Hinchcliff, Jordan S Pober, Yuval Kluger, Richard A Flavell
Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC...
September 12, 2023: Proceedings of the National Academy of Sciences of the United States of America
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JOURNAL ARTICLE
Eleanna Kaffe, Manolis Roulis, Jun Zhao, Rihao Qu, Esen Sefik, Haris Mirza, Jing Zhou, Yunjiang Zheng, Georgia Charkoftaki, Vasilis Vasiliou, Daniel F Vatner, Wajahat Z Mehal, Yuval Kluger, Richard A Flavell
Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD)...
August 31, 2023: Cell
#12
JOURNAL ARTICLE
Michael Chiorazzi, Jan Martinek, Bradley Krasnick, Yunjiang Zheng, Keenan J Robbins, Rihao Qu, Gabriel Kaufmann, Zachary Skidmore, Melani Juric, Laura A Henze, Frederic Brösecke, Adam Adonyi, Jun Zhao, Liang Shan, Esen Sefik, Jacqueline Mudd, Ye Bi, S Peter Goedegebuure, Malachi Griffith, Obi Griffith, Abimbola Oyedeji, Sofia Fertuzinhos, Rolando Garcia-Milian, Daniel Boffa, Frank Detterbeck, Andrew Dhanasopon, Justin Blasberg, Benjamin Judson, Scott Gettinger, Katerina Politi, Yuval Kluger, Karolina Palucka, Ryan C Fields, Richard A Flavell
BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME...
July 2023: Journal for Immunotherapy of Cancer
#13
JOURNAL ARTICLE
Goran Micevic, Andrew Daniels, Richard A Flavell
No abstract text is available yet for this article.
July 20, 2023: British Journal of Dermatology
#14
JOURNAL ARTICLE
Goran Micevic, Andrew Daniels, Karine Flem-Karlsen, Koonam Park, Ronan Talty, Meaghan McGeary, Haris Mirza, Holly N Blackburn, Esen Sefik, Julie F Cheung, Noah I Hornick, Lilach Aizenbud, Nikhil S Joshi, Harriet Kluger, Akiko Iwasaki, Marcus W Bosenberg, Richard A Flavell
Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7Rhi tumor-specific CD8+ population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses...
July 25, 2023: Proceedings of the National Academy of Sciences of the United States of America
#15
JOURNAL ARTICLE
Zhiqiang Xiao, Shanshan Wang, Yixia Tian, Wenkai Lv, Hao Sheng, Mingjie Zhan, Qiongxiao Huang, Zhanpeng Zhang, Leqing Zhu, Chuyun Zhu, Hui Zhong, Qiong Wen, Zonghua Liu, Jingyi Tan, Yan Xu, Meixiang Yang, Yumei Liu, Richard A Flavell, Quanli Yang, Guangchao Cao, Zhinan Yin
γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs...
June 23, 2023: Cell Reports
#16
JOURNAL ARTICLE
Theivanthiran Balamayooran, Sanjay Batra, Gayathriy Balamayooran, Shanshan Cai, Koichi S Kobayashi, Richard A Flavell, Samithamby Jeyaseelan
No abstract text is available yet for this article.
June 21, 2023: Infection and Immunity
#17
JOURNAL ARTICLE
Kaixin He, Tingting Wan, Decai Wang, Ji Hu, Tingyue Zhou, Wanyin Tao, Zheng Wei, Qiao Lu, Rongbin Zhou, Zhigang Tian, Richard A Flavell, Shu Zhu
The intestinal epithelial cells (IECs) constitute the primary barrier between host cells and numerous foreign antigens; it is unclear how IECs induce the protective immunity against pathogens while maintaining the immune tolerance to food. Here, we found IECs accumulate a less recognized 13-kD N-terminal fragment of GSDMD that is cleaved by caspase-3/7 in response to dietary antigens. Unlike the 30-kD GSDMD cleavage fragment that executes pyroptosis, the IEC-accumulated GSDMD cleavage fragment translocates to the nucleus and induces the transcription of CIITA and MHCII molecules, which in turn induces the Tr1 cells in upper small intestine...
June 9, 2023: Cell
#18
JOURNAL ARTICLE
Chenbo Ding, Zhibin Yu, Esen Sefik, Jing Zhou, Eleanna Kaffe, Gaoyang Wang, Bin Li, Richard A Flavell, Weiguo Hu, Youqiong Ye, Hua-Bing Li
Regulatory T (Treg ) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating Treg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver Treg -expressed non-protein-coding RNA), which was specifically expressed in the nucleus of Treg cells and increased with aging. Treg -specific deletion of Altre did not affect Treg homeostasis and function in young mice but caused Treg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice...
June 5, 2023: Nature aging
#19
Zheng Wei, Joonseok Oh, Richard A Flavell, Jason M Crawford
No abstract text is available yet for this article.
May 25, 2023: Nature
#20
JOURNAL ARTICLE
Elena Kotsiliti, Valentina Leone, Svenja Schuehle, Olivier Govaere, Hai Li, Monika J Wolf, Helena Horvatic, Sandra Bierwirth, Jana Hundertmark, Donato Inverso, Laimdota Zizmare, Avital Sarusi-Portuguez, Revant Gupta, Tracy O'Connor, Anastasios D Giannou, Ahmad Mustafa Shiri, Yehuda Schlesinger, Maria Garcia Beccaria, Charlotte Rennert, Dominik Pfister, Rupert Öllinger, Iana Gadjalova, Pierluigi Ramadori, Mohammad Rahbari, Nuh Rahbari, Marc E Healy, Mirian Fernández-Vaquero, Neda Yahoo, Jakob Janzen, Indrabahadur Singh, Chaofan Fan, Xinyuan Liu, Monika Rau, Martin Feuchtenberger, Eva Schwaneck, Sebastian J Wallace, Simon Cockell, John Wilson-Kanamori, Prakash Ramachandran, Celia Kho, Timothy J Kendall, Anne-Laure Leblond, Selina J Keppler, Piotr Bielecki, Katja Steiger, Maike Hofmann, Karsten Rippe, Horst Zitzelsberger, Achim Weber, Nisar Malek, Tom Luedde, Mihael Vucur, Hellmut G Augustin, Richard Flavell, Oren Parnas, Roland Rad, Olivier Pabst, Neil C Henderson, Samuel Huber, Andrew Macpherson, Percy Knolle, Manfred Claassen, Andreas Geier, Christoph Trautwein, Kristian Unger, Eran Elinav, Ari Waisman, Zeinab Abdullah, Dirk Haller, Frank Tacke, Quentin M Anstee, Mathias Heikenwalder
BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed...
August 2023: Journal of Hepatology
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