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| Open AccessPost-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia
The post-resolution phase of inflammation is not simply a linear path towards cessation of immune response but rather a regulated process involving fluctuating immune activity. Here authors show a pivotal role for post-resolution macrophages in driving a wave of T cell recruitment and activation via prostaglandin E2 and α-integrin signalling during the resolution phase of murine pneumococcal pneumonia.
- Karen T. Feehan
- , Hannah E. Bridgewater
- & Derek W. Gilroy
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Article
| Open AccessCD5L as a promising biological therapeutic for treating sepsis
Authors explore the utility of CD5L for treating experimental sepsis. CD5L deficiency exacerbates experimental sepsis. Conversely, administration of recombinant CD5L in WT mice augments neutrophil function, enhances bacterial control, and mitigates inflammation, leading to substantial improvements in disease outcomes.
- Liliana Oliveira
- , M. Carolina Silva
- & Alexandre M. Carmo
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Article
| Open AccessInflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants
HIV exposed but uninfected infants may face an increased risk of serious infection and mortality. In this work, the authors utilise a cohort from rural Zimbabwe to explore the biological mechanisms underlying infant mortality.
- Ceri Evans
- , Kuda Mutasa
- & Andrew J. Prendergast
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Article
| Open AccessImprovement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection
Post-acute sequelae of COVID (PASC) or long-COVID can affect a proportion of those infected but this is not well understood. Here the authors perform a single cell transcriptomics analysis of immune cells from long-COVID patients at 24 months and find that cell changes observed at 3 and 8 months do not persist to 24 months.
- Chansavath Phetsouphanh
- , Brendan Jacka
- & Gail V. Matthews
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Article
| Open AccessDevelopmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8+ T cells in murine models of inflammation
The heterogeneity in naive CD8+ T cells is essential for diverse immune responses. Here the authors show that variations in developmental self-reactivity of CD8+ T cells influence their differentiation into Tc17 cells in inflammatory conditions.
- Gil-Woo Lee
- , Young Ju Kim
- & Jae-Ho Cho
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Article
| Open AccessPCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor
Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to an increase of LDL cholesterol in blood. Here the authors show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor.
- Dasom Shin
- , Soungchan Kim
- & Hyo-Soo Kim
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Article
| Open AccessGasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation
Gasdermin D (GSDMD) is a pore forming protein activated by inflammasome derived caspases. Here the authors characterize the function of GSDMD in mouse influenza virus infection and show that immunopathology is reduced in the absence of GSDMD and involves changes in neutrophil function.
- Samuel Speaks
- , Matthew I. McFadden
- & Jacob S. Yount
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Article
| Open AccessThe IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis
Current animal models of periodontitis are biased towards sample collection from gingival tissue, while other periodontal structures may play similarly important role in the initiation and maintenance of inflammation. Here authors present a model that enables a more comprehensive and longitudinal assessment of periodontal tissues, which points to a pivotal role for the peri-root tissues and an IL-33/ST2 axis in the pathogenesis.
- Anhao Liu
- , Mikihito Hayashi
- & Tomoki Nakashima
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Article
| Open AccessIKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model
Loss of function mutation studies has provided insights into regulatory T-cell biology. Here Cardinez et al explore the effects of a murine Ikbkb (IKK2) gain of function model and show IKK2 activity results in the expansion of regulatory T cells with partial effector function and suggest an IKK2 dose-dependent relation between psoriatic immunopathology and psoriatic arthritis.
- Chelisa Cardinez
- , Yuwei Hao
- & Matthew C. Cook
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Article
| Open AccessAxl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis
The TAM tyrosine kinases, Axl and MerTK, have been implicated in rheumatoid arthritis (RA). Here, using a synovial tissue bioresource of patients with RA, the authors describe how Axl and MerTK expression and function are linked to synovial histopathology, disease activity, and therapeutic intervention with IL-6 inhibitors.
- Alessandra Nerviani
- , Marie-Astrid Boutet
- & Costantino Pitzalis
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Article
| Open AccessStem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice
The role of stem Leydig cells in restoration of male fertility after acute injury is not clear. In an acute injury mouse model of testicular torsion, the authors show that Stem Leydig cells can restore testicular immunological homeostasis by mitochondria transfer to macrophages in a TRPM7-mediated manner.
- Ani Chi
- , Bicheng Yang
- & Min Zhang
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| Open AccessRHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling
Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that primarily responds to ligation of bacterial lipopolysaccharide. Here the authors suggest the intramembrane protease RHBDL4 as a regulator of TLR4 signaling.
- Julia D. Knopf
- , Susanne S. Steigleder
- & Marius K. Lemberg
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Article
| Open AccessNFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins
The immunobiology regulating the contribution of monocytes to severe COVID-19 immunopathology are not fully understood. Here the authors show that SARS-CoV-2 S1 and NP proteins differentially promote NLRP3/NLRC4 inflammasome activity, differentiation, and T cell-priming function of monocytes.
- Ilya Tsukalov
- , Ildefonso Sánchez-Cerrillo
- & Enrique Martin-Gayo
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Article
| Open AccessTargeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Article
| Open AccessEvidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis
Podoconiosis is triggered by long term barefoot exposure to volcanic red clay soil. Here, Negash et al characterise the immune profile of podoconiosis patients to show this disease is associated with high levels of immune activation and inflammation.
- Mikias Negash
- , Menberework Chanyalew
- & Melanie J. Newport
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Article
| Open AccessA single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Article
| Open AccessEFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death
Physiologically, the host suppresses intestinal epithelial cell death to prevent intestinal inflammation. Here, the authors show that EF-hand domain-containing protein D2 (EFHD2) endogenously suppresses intestinal epithelial cell death by blocking TNFR1 internalization and protects the intestine from excessive inflammation.
- Jiacheng Wu
- , Xiaoqing Xu
- & Xuetao Cao
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Article
| Open AccessStructural basis for the oligomerization-facilitated NLRP3 activation
NLRP3 is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Here, the authors determined Cryo-EM structures of human NLRP3 in its closed and open states, elucidating the mechanism of NLRP3 inflammasome activation.
- Xiaodi Yu
- , Rosalie E. Matico
- & Sujata Sharma
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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessEosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase
Eosinophils are traditional immune effectors involved in tissue homeostasis. In this study, eosinophils emerge as key regulators of bone homeostasis by interacting with osteoclasts, inhibiting their differentiation and pathological bone loss.
- Darja Andreev
- , Katerina Kachler
- & Aline Bozec
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Article
| Open Access5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis
There is a strong need for the development of effective and safe disease-modifying osteoarthritis drugs. Here, the authors show that 5-ASA, an anti-inflammatory drug used for ulcerative colitis, shows promise in treating osteoarthritis in mice by improving cartilage and reducing inflammation even when administered at late stages of disease.
- Jihee Kim
- , Gina Ryu
- & Soo Young Lee
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Article
| Open AccessVEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation
Acquired mutations of the gene UBA1 occurring in myeloid cells that result in the expression of impaired isoforms of the enzyme E1 have been described in patients with a severe adult onset auto-inflammatory syndrome called VEXAS. Here the authors profile patients with UBA1 mutations presenting with or without VEXAS disease and show VEXAS disease is characterized by inflammasome activation and monocyte dysregulation.
- Olivier Kosmider
- , Céline Possémé
- & Benjamin Terrier
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Article
| Open AccessSingle-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade
Single cell profiling of tissue from patients undergoing therapy has the potential to identify drug-induced immune changes. Here the authors show a skin scRNA-seq study of psoriasis patients treated with an IL-23 inhibitor and characterize changes in cell states during early treatment.
- Luc Francis
- , Daniel McCluskey
- & Satveer K. Mahil
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Article
| Open AccessPRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury
Excessive inflammatory responses contribute to severe malaria. Here, Du et al, show that the protein tyrosine phosphatase PRL2 contributes to neutrophil activation and extracellular trap release in an experimental model of severe malaria.
- Xinyue Du
- , Baiyang Ren
- & Zhaojun Wang
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Article
| Open AccessMitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging
Dysregulated autophagy and mitochondrial function are two well-described hallmarks of aging. Here, the authors describe an unexpected age-associated upregulation of mitophagy in response to neuroinflammation triggered by leaked mtDNA.
- Juan Ignacio Jiménez-Loygorri
- , Beatriz Villarejo-Zori
- & Patricia Boya
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Article
| Open AccessA cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis
Viruses have evolved specific mechanisms to reduce programmed cell death in order to prolong survival. Here the authors show a mouse cytomegalovirus (MCMV) encoded protein that inhibits pyroptosis, proinflammatory cytokine release and the assembly of inflammasomes.
- Yingqi Deng
- , Eleonore Ostermann
- & Wolfram Brune
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Article
| Open AccessAltered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease
Cigarette smoking is an established risk factor for inflammatory bowel disease. The authors suggest that smoking may affect the risk of Crohn’s disease and ulcerative colitis by modulating the DNA methylation status of the DNMT3A, LTA/TNF, and AHRR region, respectively.
- Han Zhang
- , Rahul Kalla
- & Xue Li
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Article
| Open AccessTargeted therapies of inflammatory diseases with intracellularly gelated macrophages in mice and rats
Membrane-decorated nanomedicines often suffer from reduced efficacy caused by membrane artefacts during the coating process. Here the authors show that intracellularly gelated macrophages preserve membrane properties, stay stable under ambient temperature, and show therapeutic effects in murine models of joint and lung inflammation.
- Cheng Gao
- , Qingfu Wang
- & Ruibing Wang
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Article
| Open AccessIKKε and TBK1 prevent RIPK1 dependent and independent inflammation
TBK1 and IKKε are involved in the regulation of a range of cellular and inflammatory processes. Here Eren and colleagues discern a role for IKKε in preventing RIPK1-dependent and RIPK1-independent inflammation in mice lacking TBK1 kinase activity.
- Remzi Onur Eren
- , Göksu Gökberk Kaya
- & Manolis Pasparakis
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Article
| Open AccessGut microbiota facilitate chronic spontaneous urticaria
Chronic spontaneous urticarial is an inflammatory skin disease which has been linked to intestinal dysbiosis. Here the authors implicate intestinal dysbiosis with the inflammatory response in a murine model of urticaria.
- Lei Zhu
- , Xingxing Jian
- & Jie Li
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Article
| Open AccessSerglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration
Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.
- Fan Chen
- , Linchuan Lei
- & Jianru Wang
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Article
| Open AccessPara-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.
- Benedict D. Michael
- , Cordelia Dunai
- & David K. Menon
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Article
| Open AccessNuclear RPSA senses viral nucleic acids to promote the innate inflammatory response
Innate immune responses are the first line of defence against viral pathogens. Here, Jiang et al show that the nuclear located 40S ribosomal protein SA senses viral nucleic acids to selectively enhance proinflammatory cytokine gene expression through epigenetic modification.
- Yan Jiang
- , Siqi Sun
- & Xuetao Cao
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Article
| Open AccessInflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).
- Danfeng Dong
- , Yuzhang Du
- & Dakang Xu
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Article
| Open AccessAcetylation is required for full activation of the NLRP3 inflammasome
The NLRP3 inflammasome is activated in two steps, priming and assembly, in response to endogenous, microbial, and other environmental danger signals. Here authors show that the assembly step is regulated by acetylation, and inhibition of this post-translational modification prevents full activation of the inflammasome.
- Yening Zhang
- , Ling Luo
- & Kai Zhao
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Article
| Open AccessActivation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (IPF) consists of lung inflammation and collagen deposition leading to reduced lung function and non-inducible mouse models are needed. Here the authors show a spontaneous mouse IPF model where Ifngr1-/-Rag2-/- mice show enhanced ILC2 activation and function along with pathology similar to IPF.
- Natsuko Otaki
- , Yasutaka Motomura
- & Kazuyo Moro
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Article
| Open AccessInterleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling
Paneth cell metaplasia (PCM) typically arises in diseases intrinsic to the gastrointestinal tract; however, whether extra intestinal diseases can trigger PCM and the mechanistic pathway by which PCM develops is unknown. Herein, the authors show in an inducible murine model of chronic myelogenous leukaemia that a systemic inflammatory state can trigger IL-33- mediated IL-9 production that leads to small intestinal remodelling and PCM.
- Chengyin Yuan
- , Aditya Rayasam
- & William R. Drobyski
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Article
| Open AccessPyroptosis inhibiting nanobodies block Gasdermin D pore formation
Pyroptosis has been implicated in many diseases with aberrant inflammation. Here, Kopp et al. characterize single-chain nanobodies targeting the human gasdermin D protein as tools to inhibit pyroptosis.
- Anja Kopp
- , Gregor Hagelueken
- & Matthias Geyer
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Article
| Open AccessProtective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis
During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin α5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.
- Ruoshui Li
- , Bijun Chen
- & Nikolaos G. Frangogiannis
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Article
| Open AccessEicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction
Systemic inflammation is recognized as a central pathobiologic feature in heart failure with preserved ejection fraction (HFpEF). Here, the authors report 70 pro- and anti-inflammatory eicosanoid and eicosanoid-related metabolites associated with HFpEF status.
- Emily S. Lau
- , Athar Roshandelpoor
- & Jennifer E. Ho
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Article
| Open AccessInflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
The immune suppression required for the resolution of acute inflammation is characterised by molecular and metabolic reprogramming of myeloid cells. Authors here show that the transcription factor ZEB1 is a key mediator of the pathway governing transition from inflammation to immunosuppression via regulating mitochondrial translation in macrophages.
- Marlies Cortés
- , Agnese Brischetto
- & Antonio Postigo
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Article
| Open AccessSEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway
Interferon-gamma (IFN-γ) is an important but not exclusive proinflammatory mediator in macrophages. Here authors show that IFN-γ-independent macrophage autoactivation involves endoplasmic reticulum (ER) stress which in turn induces the GTP-binding protein Septin2 to limit inflammation via a negative feedback loop.
- Beibei Fu
- , Yan Xiong
- & Haibo Wu
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Article
| Open AccessTLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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Matters Arising
| Open AccessReply to: Failure to apply standard limit-of-detection or limit-of-quantitation criteria to specialized pro-resolving mediator analysis incorrectly characterizes their presence in biological samples
- Jesmond Dalli
- & Esteban A. Gomez
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Article
| Open AccessCryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open AccessSingle cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs
Mathematical tools can be used to help identify pathological features from images of diseased lungs. Here, the authors used mathematical tools combined with high resolution multiplex imaging mass cytometry to show an association between immature neutrophils, CD8 T cells and proliferating alveolar epithelial cells in areas of maximal alveolar damage in COVID-19 lungs.
- Praveen Weeratunga
- , Laura Denney
- & Ling-Pei Ho
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Article
| Open AccessPeripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (CD) is a rare and potentially fatal lymphoproliferative disorder. Authors here establish a mouse xenotransplantation model of the “not otherwise specified” subtype of the disease and show that the chemokine CXCL13 plays a pivotal role in the pathogenesis and likely produced by peripheral helper cells, which expand upon engraftment.
- Takuya Harada
- , Yoshikane Kikushige
- & Kazuyuki Yoshizaki
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Article
| Open AccessUbiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions
Vascular endothelial cadherin (VE-cadherin), endothelial cell-cell adhesive protein maintains blood vessel barrier integrity and vascular homeostasis. Here, the authors show that infectious bacterial toxin activates ubiquitin ligase CHFR which in turn degrades VEcadherin via ubiquitylation in endothelial cells to cause vascular injury.
- Chinnaswamy Tiruppathi
- , Dong-Mei Wang
- & Asrar B. Malik
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Article
| Open AccessFibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano