journal
https://read.qxmd.com/read/38536100/cracking-the-nlrp3-code-pioneering-precision-medicine-for-inflammation
#1
JOURNAL ARTICLE
Alexander N R Weber, Maria Mateo Tortola, Jasmin B Kuemmerle-Deschner
Precisely diagnosing and effectively treating cryopyrin-associated periodic syndrome (CAPS), an inflammatory condition linked to gain-of-function NLRP3 inflammasome mutations, poses challenges. A novel classification approach may help inform therapeutic decisions and offer valuable insights into broader inflammatory conditions (Cosson et al. J. Exp. Med. 2024. https://doi.org/10.1084/jem.20231200).
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38530241/functional-diversity-of-nlrp3-gain-of-function-mutants-associated-with-caps-autoinflammation
#2
JOURNAL ARTICLE
Camille Cosson, Romane Riou, Danish Patoli, Tingting Niu, Amaury Rey, Marine Groslambert, Charlotte De Rosny, Elodie Chatre, Omran Allatif, Thomas Henry, Fabienne Venet, Florian Milhavet, Guilaine Boursier, Alexandre Belot, Yvan Jamilloux, Etienne Merlin, Agnès Duquesne, Gilles Grateau, Léa Savey, Alexandre Thibault Jacques Maria, Anne Pagnier, Solène Poutrel, Olivier Lambotte, Coralie Mallebranche, Samuel Ardois, Olivier Richer, Irène Lemelle, Frédéric Rieux-Laucat, Brigitte Bader-Meunier, Zahir Amoura, Isabelle Melki, Laurence Cuisset, Isabelle Touitou, Matthias Geyer, Sophie Georgin-Lavialle, Bénédicte F Py
NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38530240/induction-of-immortal-like-and-functional-car-t-cells-by-defined-factors
#3
JOURNAL ARTICLE
Lixia Wang, Gang Jin, Qiuping Zhou, Yanyan Liu, Xiaocui Zhao, Zhuoyang Li, Na Yin, Min Peng
Long-term antitumor efficacy of chimeric antigen receptor (CAR) T cells depends on their functional persistence in vivo. T cells with stem-like properties show better persistence, but factors conferring bona fide stemness to T cells remain to be determined. Here, we demonstrate the induction of CAR T cells into an immortal-like and functional state, termed TIF. The induction of CARTIF cells depends on the repression of two factors, BCOR and ZC3H12A, and requires antigen or CAR tonic signaling. Reprogrammed CARTIF cells possess almost infinite stemness, similar to induced pluripotent stem cells while retaining the functionality of mature T cells, resulting in superior antitumor effects...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38530239/piezo1-channels-restrain-ilc2s-and-regulate-the-development-of-airway-hyperreactivity
#4
JOURNAL ARTICLE
Benjamin P Hurrell, Stephen Shen, Xin Li, Yoshihiro Sakano, Mohammad Hossein Kazemi, Christine Quach, Pedram Shafiei-Jahani, Kei Sakano, Homayon Ghiasi, Omid Akbari
Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here, we report that Piezo1 channels repress group 2 innate lymphoid cell (ILC2)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we found that Piezo1 engagement reduces ILC2 oxidative metabolism...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38517332/a-tbk1-variant-causes-autophagolysosomal-and-motoneuron-pathology-without-neuroinflammation-in-mice
#5
JOURNAL ARTICLE
David Brenner, Kirsten Sieverding, Jahnavi Srinidhi, Susanne Zellner, Christopher Secker, Rüstem Yilmaz, Julia Dyckow, Shady Amr, Anna Ponomarenko, Esra Tunaboylu, Yasmin Douahem, Joana S Schlag, Lucía Rodríguez Martínez, Georg Kislinger, Cornelia Niemann, Karsten Nalbach, Wolfgang P Ruf, Jonathan Uhl, Johanna Hollenbeck, Lucas Schirmer, Alberto Catanese, Christian S Lobsiger, Karin M Danzer, Deniz Yilmazer-Hanke, Christian Münch, Philipp Koch, Axel Freischmidt, Martina Fetting, Christian Behrends, Rosanna Parlato, Jochen H Weishaupt
Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38512136/antigen-independent-autonomous-b-cell-receptor-signaling-drives-activated-b-cell-dlbcl
#6
JOURNAL ARTICLE
Janneke A Eken, Marvyn T Koning, Kristyna Kupcova, Julieta H Sepúlveda Yáñez, Ruben A L de Groen, Edwin Quinten, Jurriaan Janssen, Cornelis A M van Bergen, Joost S P Vermaat, Arjen Cleven, Marcelo A Navarrete, Bauke Ylstra, Daphne de Jong, Ondrej Havranek, Hassan Jumaa, Hendrik Veelken
Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38506708/dietary-fiber-is-a-critical-determinant-of-pathologic-ilc2-responses-and-intestinal-inflammation
#7
JOURNAL ARTICLE
Mohammad Arifuzzaman, Tae Hyung Won, Hiroshi Yano, Jazib Uddin, Elizabeth R Emanuel, Elin Hu, Wen Zhang, Ting-Ting Li, Wen-Bing Jin, Alex Grier, Sanchita Kashyap, Chun-Jun Guo, Frank C Schroeder, David Artis
Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38502057/distinct-molecular-profiles-drive-multifaceted-characteristics-of-colorectal-cancer-metastatic-seeds
#8
JOURNAL ARTICLE
Yuanyuan Zhao, Bing Zhang, Yiming Ma, Mengmeng Guo, Fuqiang Zhao, Jianan Chen, Bingzhi Wang, Hua Jin, Fulai Zhou, Jiawei Guan, Qian Zhao, Qian Liu, Hongying Wang, Fangqing Zhao, Xia Wang
Metastasis of primary tumors remains a challenge for early diagnosis and prevention. The cellular properties and molecular drivers of metastatically competent clones within primary tumors remain unclear. Here, we generated 10-16 single cell-derived lines from each of three colorectal cancer (CRC) tumors to identify and characterize metastatic seeds. We found that intrinsic factors conferred clones with distinct metastatic potential and cellular communication capabilities, determining organ-specific metastasis...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38497819/competitive-fungal-commensalism-mitigates-candidiasis-pathology
#9
JOURNAL ARTICLE
Jarmila Sekeresova Kralova, Catalina Donic, Bareket Dassa, Ilana Livyatan, Paul Mathias Jansen, Shifra Ben-Dor, Lena Fidel, Sébastien Trzebanski, Lian Narunsky-Haziza, Omer Asraf, Ori Brenner, Hagit Dafni, Ghil Jona, Sigalit Boura-Halfon, Noa Stettner, Eran Segal, Sascha Brunke, Yitzhak Pilpel, Ravid Straussman, David Zeevi, Petra Bacher, Bernhard Hube, Neta Shlezinger, Steffen Jung
The mycobiota are a critical part of the gut microbiome, but host-fungal interactions and specific functional contributions of commensal fungi to host fitness remain incompletely understood. Here, we report the identification of a new fungal commensal, Kazachstania heterogenica var. weizmannii, isolated from murine intestines. K. weizmannii exposure prevented Candida albicans colonization and significantly reduced the commensal C. albicans burden in colonized animals. Following immunosuppression of C. albicans colonized mice, competitive fungal commensalism thereby mitigated fatal candidiasis...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38497818/one-in-one-out-commensal-fungus-protects-against-infection
#10
JOURNAL ARTICLE
Rebecca A Drummond
Gut-resident fungi have a broad influence over health and disease. In this issue of JEM, Sekeresova Kralova et al. (https://doi.org/10.1084/jem.20231686) identify a commensal yeast that displaced fungal pathogen Candida albicans and protected against subsequent invasive infections that originate from the gut.
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38448036/human-neutrophils-drive-skin-autoinflammation-by-releasing-interleukin-il-26
#11
JOURNAL ARTICLE
Alessia Baldo, Jeremy Di Domizio, Ahmad Yatim, Sophie Vandenberghe-Dürr, Raphael Jenelten, Anissa Fries, Lorenzo Grizzetti, François Kuonen, Carle Paul, Robert L Modlin, Curdin Conrad, Michel Gilliet
Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils...
May 6, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38517331/icos-costimulation-in-combination-with-ctla-4-blockade-remodels-tumor-associated-macrophages-toward-an-antitumor-phenotype
#12
JOURNAL ARTICLE
Naveen Sharma, Xiaozhou Fan, Oluwatomisin T Atolagbe, Zhongqi Ge, Kelly N Dao, Padmanee Sharma, James P Allison
We have previously demonstrated synergy between ICOS costimulation (IVAX; ICOSL-transduced B16-F10 cellular vaccine) and CTLA-4 blockade in antitumor therapy. In this study, we employed CyTOF and single-cell RNA sequencing and observed significant remodeling of the lymphoid and myeloid compartments in combination therapy. Compared with anti-CTLA-4 monotherapy, the combination therapy enriched Th1 CD4 T cells, effector CD8 T cells, and M1-like antitumor proinflammatory macrophages. These macrophages were critical to the therapeutic efficacy of anti-CTLA-4 combined with IVAX or anti-PD-1...
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38477873/xiaoyu-hu-let-the-data-guide-you
#13
JOURNAL ARTICLE
Lucie Van Emmenis
Xiaoyu Hu is a professor and director of the Institute for Immunology at Tsinghua University. Her lab is interested in understanding the molecular mechanisms underlying the transcriptional, translational, and metabolic mechanisms of the key cell types involved in host defense and inflammatory responses: macrophages and intestinal epithelial cells (IECs). We recently spoke with Xiaoyu about her current work, the benefits of a multidisciplinary team, and how being part of journal editorial boards brings her intellectual stimulation and inspiration for her own lab...
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38451255/the-anatomic-basis-of-leptomeningeal-metastasis
#14
REVIEW
Morgan E Freret, Adrienne Boire
Leptomeningeal metastasis (LM), or spread of cancer to the cerebrospinal fluid (CSF)-filled space surrounding the central nervous system, is a fatal complication of cancer. Entry into this space poses an anatomical challenge for cancer cells; movement of cells between the blood and CSF is tightly regulated by the blood-CSF barriers. Anatomical understanding of the leptomeninges provides a roadmap of corridors for cancer entry. This Review describes the anatomy of the leptomeninges and routes of cancer spread to the CSF...
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38442272/vegf-c-prophylaxis-favors-lymphatic-drainage-and-modulates-neuroinflammation-in-a-stroke-model
#15
JOURNAL ARTICLE
Ligia Simoes Braga Boisserand, Luiz Henrique Geraldo, Jean Bouchart, Marie-Renee El Kamouh, Seyoung Lee, Basavaraju G Sanganahalli, Myriam Spajer, Shenqi Zhang, Sungwoon Lee, Maxime Parent, Yuechuan Xue, Mario Skarica, Xiangyun Yin, Justine Guegan, Kevin Boyé, Felipe Saceanu Leser, Laurent Jacob, Mathilde Poulet, Mingfeng Li, Xiodan Liu, Sofia E Velazquez, Ruchith Singhabahu, Mark E Robinson, Michael H Askenase, Artem Osherov, Nenad Sestan, Jiangbing Zhou, Kari Alitalo, Eric Song, Anne Eichmann, Lauren H Sansing, Helene Benveniste, Fahmeed Hyder, Jean-Leon Thomas
Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intracerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells...
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38442271/meningeal-lymphatics-can-influence-stroke-outcome
#16
COMMENT
Gou Young Koh, Donald M McDonald
Meningeal lymphatics are conduits for cerebrospinal fluid drainage to lymphatics and lymph nodes in the neck. In this issue of JEM, Boisserand et al. (https://doi.org/10.1084/jem.20221983) provide evidence that expansion of meningeal lymphatics protects against ischemic stroke.
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38442270/nadph-oxidase-exerts-a-b-cell-intrinsic-contribution-to-lupus-risk-by-modulating-endosomal-tlr-signals
#17
JOURNAL ARTICLE
Shuozhi Liu, Jonathan Lagos, Natali M Shumlak, Andrea D Largent, Sebastien T E Lewis, Ursula Holder, Samuel W Du, Yifan Liu, Baidong Hou, Mridu Acharya, Shaun W Jackson
Genome-wide association studies in systemic lupus erythematosus (SLE) have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to disease pathogenesis. The prevailing model holds that reduced NOX2 activity promotes SLE via defective efferocytosis, the immunologically silent clearance of apoptotic cells. Here, we describe a parallel B cell-intrinsic mechanism contributing to breaks in tolerance. In keeping with an important role for B cell Toll-like receptor (TLR) pathways in lupus pathogenesis, NOX2-deficient B cells exhibit enhanced signaling downstream of endosomal TLRs, increased humoral responses to nucleic acid-containing antigens, and the propensity toward humoral autoimmunity...
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38442269/macro-clusters-cd301b-dcs-prime-th2-responses
#18
JOURNAL ARTICLE
Hanna Abberger, Joanna R Groom
In this issue of JEM, Lyons-Cohen et al. (https://doi.org/10.1084/jem.20231282) reveal that lymph node macro-clusters provide a spatial niche where CD301b+ cDC2s and CD4+ T cells interact. These integrin-mediated cellular hubs promote enhanced co-stimulation and cytokine signaling to drive Th2 differentiation.
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38442268/site-specific-regulation-of-th2-differentiation-within-lymph-node-microenvironments
#19
JOURNAL ARTICLE
Miranda R Lyons-Cohen, Elya A Shamskhou, Michael Y Gerner
T helper 2 (Th2) responses protect against pathogens while also driving allergic inflammation, yet how large-scale Th2 responses are generated in tissue context remains unclear. Here, we used quantitative imaging to investigate early Th2 differentiation within lymph nodes (LNs) following cutaneous allergen administration. Contrary to current models, we observed extensive activation and "macro-clustering" of early Th2 cells with migratory type-2 dendritic cells (cDC2s), generating specialized Th2-promoting microenvironments...
April 1, 2024: Journal of Experimental Medicine
https://read.qxmd.com/read/38442267/cholesterol-25-hydroxylase-mediates-neuroinflammation-and-neurodegeneration-in-a-mouse-model-of-tauopathy
#20
JOURNAL ARTICLE
Danira Toral-Rios, Justin M Long, Jason D Ulrich, Jinsheng Yu, Michael R Strickland, Xianlin Han, David M Holtzman, Anil G Cashikar, Steven M Paul
Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a "disease-associated microglia" signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene...
April 1, 2024: Journal of Experimental Medicine
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