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| 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
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| Open AccessTargeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
In this work, the authors report a drug class based on an ancient innate defense fold. Inspired by Nature’s anti-infective strategies, this peptide-based drug targets systemic inflammation via multiple molecular interactions, enhancing effectiveness
- Ganna Petruk
- , Manoj Puthia
- & Artur Schmidtchen
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| Open AccessOrai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
The regulation and intracellular transport of Ca2+ in immune cells involves Ca2+ release-activated Ca2+ (CRAC) channels. Here the authors show targeting CRAC components Orai1 and Orai2 modulates pulmonary ILC2 cells altering their metabolism, function and is linked to alleviation of immunopathology in a murine model of allergic airway disease.
- Emily Howard
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessCREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
The mechanistic functions of neutrophils in skin inflammation are not fully understood. Here the authors use human psoriasis samples and a mouse model of skin inflammation to study neutrophils and find a CXCR4hi population of NET-forming, phagocytic neutrophils whose induction depends on the transcription factor CREB1.
- Jiaoling Chen
- , Yaxing Bai
- & Shuai Shao
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| Open AccessNLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity
Bacterial infection of immune cells can result in engagement of different immunological pathways. Here the authors show that a Pseudomonas aeruginosa type three secretion system exoenzyme is linked to the differential selection of inflammasome usage between macrophages and neutrophils.
- Martin S. Minns
- , Karl Liboro
- & Eric Pearlman
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Article
| Open AccessA CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans
Extra-intestinal “creeping fat” is a hallmark of Crohn’s disease. Here, using single-cell transcriptomics and lipid metabolomics, the authors identify a subset of mesenchymal stem cells that promote adipogenesis in creeping fat formation.
- Fengfei Wu
- , Fangting Wu
- & Lan Bai
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Article
| Open AccessPro-phagocytic function and structural basis of GPR84 signaling
GPR84 is an important GPCR regulating macrophage function. Here, the authors show the pro-phagocytic function of the GPR84-Gi signaling axis in native macrophages and determine a cryo-EM structure of the GPR84-Gi complex with a synthetic agonist.
- Xuan Zhang
- , Yujing Wang
- & Cheng Zhang
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| Open Accessγδ T cells control murine skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei infection
Trypansome brucei infection can result in colonisation of the skin but how this impacts the skin architecture and immune response has not been fully resolved. Here the authors apply a spatially resolved single cell transcriptomics approach in a murine model of infection, and suggest a role for IL-17- producing γδ T cells in the immune response to T. brucei skin infection.
- Juan F. Quintana
- , Matthew C. Sinton
- & Annette MacLeod
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Article
| Open AccessRORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation
IL-17 secreting Th17 cells have established roles in numerous immune-pathologies but paradoxically are required homeostatically in the maintenance of the intestinal barrier. Here the authors establish Raftlin-1 in the recruitment of phospholipids that are linked to the emergence of pathogenic Th17 cells in animal models of bowel inflammation.
- Amir Kumar Singh
- , Ritesh Kumar
- & K. Venuprasad
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| Open AccessA single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia
Achalasia is a rare motility disorder of the esophagus resulting from abnormal immune responses, but the immunologic mechanism is unclear. Here the authors use scRNA-seq of PBMC and esophageal lower sphincter tissue and find C1QC+ macrophages and tissue-resident memory T cells with expanded compositions and altered transcriptional profiles in achalasia.
- Zu-Qiang Liu
- , Hao Dai
- & Quan-Lin Li
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Article
| Open AccessEffect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes
A beneficial effect of parasitic worms on metabolic health has been postulated based on epidemiological and animal studies. Here, the authors show in a phase I clinical trial that treatment of people at risk of type 2 diabetes with hookworms is safe and may improve key measures of metabolic health.
- Doris R. Pierce
- , Malcolm McDonald
- & Paul R. Giacomin
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Article
| Open AccessLILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis
Inhibition of immunocyte infiltration and activation has been suggested to ameliorate hepatic inflammation and fibrosis in nonalcoholic steatohepatitis. Here, the authors show PirB/LILRB2 regulates the migration of macrophages during NASH by binding with ANGPTL8, which is involved in the regulation of NASH development.
- Dan-Pei Li
- , Li Huang
- & Xue-Feng Yu
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| Open AccessIL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation
The turnover of interleukin-1β, a cytokine that plays important roles in both physiologic and pathologic inflammatory processes, is regulated by proteolytic maturation of the pro-form and by ubiquitin-mediated degradation. Here authors identify the specific ubiquitin E3 ligases that form an active complex with UBE2L3, a ubiquitin conjugating enzyme, that target pro-IL-1β for proteasomal breakdown.
- Vishwas Mishra
- , Anna Crespo-Puig
- & Avinash R. Shenoy
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| Open AccessChronic inflammation, neutrophil activity, and autoreactivity splits long COVID
Post-acute sequelae of COVID-19 (PASC) has heterogenous presentation and complex etiology. Here the authors profile peripheral blood of patients with PASC and analyze by machine-learning to identify immune and serology features that allow the stratification of PASC into inflammatory and non-inflammatory types for better diagnosis and therapy-planning.
- Matthew C. Woodruff
- , Kevin S. Bonham
- & Ignacio Sanz
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| Open AccessWhole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Rosacea is a common, multi-factorial chronic inflammatory skin disorder. Here authors provide evidence of genetic predisposition by whole genome sequencing and whole exome sequencing of samples from familial cases, and by recapitulating a recurrent mutation in the LRRC4 gene in a mouse model, they find that neuron-derived vasoactive intestinal peptide is an important pathogenic factor for neurogenic inflammation in rosacea.’
- Zhili Deng
- , Mengting Chen
- & Ji Li
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| Open AccessToll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses
Compared to germinal centres, extrafollicular plasmablast responses are thought to produce lower affinity antibodies, offering little protection from infection. Here authors show in an influenza infection and immunization mouse model that extrafollicular responses could yield protective antibodies, and that their development depends on signals provided via Toll-like receptor stimulation.
- Jonathan H. Lam
- & Nicole Baumgarth
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Article
| Open AccessSingle cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome
Paediatric acute respiratory distress syndrome (pARDS) is associated with significant mortality and morbidity. Here the authors use single cell sequencing of tracheal aspirate samples from children with pARDS and characterise immune phenotypes and associations with infection stage and pathogen.
- Tim Flerlage
- , Jeremy Chase Crawford
- & Paul G. Thomas
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| Open AccessTrans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation
Increased susceptibility to gastrointestinal infections and colitis can be driven by a failure to maintain intestinal homeostasis. Here, using a forward genetic screen, Song et al. identify and characterise the role of TVP23B in Paneth cell and goblet cell function, and its impact on colitis.
- Ran Song
- , William McAlpine
- & Emre E. Turer
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| Open AccessDimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon
Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.
- Tristram A. J. Ryan
- , Alexander Hooftman
- & Luke A. J. O’Neill
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| Open AccessSingle cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis
Changes in Psoriasis and other inflammatory skin diseases during severity stages can be investigated using single cell and spatial transcriptomics. Here the authors compare different inflammatory skin diseases to emphasise differences in immune cells and inflammatory markers particularly keratinocytes and fibroblasts.
- Feiyang Ma
- , Olesya Plazyo
- & Johann E. Gudjonsson
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| Open AccessPersistent serum protein signatures define an inflammatory subcategory of long COVID
Long COVID or post-acute sequelae of SARS-CoV-2 is defined by persisting chronic symptoms following acute SARS-CoV-2 infection but represent an aetiologically diverse group of disorders. Here authors identify molecularly distinct subtypes, including a form with persistent inflammation, via longitudinal analysis of serum proteome.
- Aarthi Talla
- , Suhas V. Vasaikar
- & Troy R. Torgerson
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| Open AccessNeutrophil-derived catecholamines mediate negative stress effects on bone
Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.
- Miriam E. A. Tschaffon-Müller
- , Elena Kempter
- & Stefan O. Reber
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| Open AccessIntrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease
Chronic kidney disease (CKD) is a disease that irreversibly leads to loss of renal function. Here, the authors demonstrate the beneficial effect of intrinsic TGF-b signaling on mitochondrial function and inflammation in the proximal tubule epithelium in response to kidney injury.
- Merve Kayhan
- , Judith Vouillamoz
- & Stellor Nlandu Khodo
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| Open AccessA ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells
NLRP3 inflammasomes trigger release of IL-1 to promote tissue injury. Here, Li et al identify a ZFYVE21-Rubicon-RNF34 (ZRR) signaling complex localizing to endosomes and modulating complement-mediated inflammasome activity in vitro and in vivo.
- Xue Li
- , Quan Jiang
- & Dan Jane-wit
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| Open AccessPPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis
IL-9-producing helper T (TH9) cells contribute to allergic inflammation. In this study, the authors demonstrate that the transcription factor PPAR-γ regulates TH9 effector function by promoting glucose metabolism and mTOR signaling in human allergic contact dermatitis.
- Nicole L. Bertschi
- , Oliver Steck
- & Christoph Schlapbach
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| Open AccessAGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling
Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.
- Xingwen Da
- , Ziyan Li
- & Qing K. Wang
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| Open AccessGlucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance
Obesity and a high-fat diet can lead to insulin resistance in a process involving macrophage-mediated inflammation of adipose tissue. Here the authors show that glucocorticoid receptor-deficient macrophages have an elevated inflammatory response which aggravates insulin resistance implicating that glucocorticoids promote insulin-sensitizing actions via adipose tissue macrophages during obesity.
- Giorgio Caratti
- , Ulrich Stifel
- & Jan P. Tuckermann
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| Open AccessLung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.
- Youn Jung Choi
- , Ji-Seung Yoo
- & Jae U. Jung
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| Open AccessTenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis
Local cues for hyperinnervation in chronic skin diseases are not fully understood. Here, the authors show that a distinct subset of dermal papillary fibroblasts promote neurite outgrowth and facilitate neuron-immune interactions through extracellular matrix remodeling in a mouse model of psoriasis
- Xiaojie Cai
- , Maoying Han
- & Honglin Wang
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Article
| Open AccessConstitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.
- Adriana A. de Jesus
- , Guibin Chen
- & Raphaela Goldbach-Mansky
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| Open AccessCTCF controls three-dimensional enhancer network underlying the inflammatory response of bone marrow-derived dendritic cells
The role of 3D genome organization is not well understood in the transcriptional regulation of dendritic cells. Here the authors show that activation of dendritic cells in vitro induces dynamic reprogramming of the chromatin looping and enhancer activity linked to changes in gene expression and implicates a role for the chromatin architecture protein CTCF in the inflammatory response of dendritic cells.
- Bobae Yang
- , Sueun Kim
- & Hyoung-Pyo Kim
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| Open AccessSerum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model
The immune response has been suggested to be involved in the pathology of Ménière’s disease. Here the authors implicate serum glucocorticoid-inducible kinase 1 as a regulator of the NLRP3 inflammasome and link to macrophage function in a model of Ménière’s disease pathology.
- Dao-Gong Zhang
- , Wen-Qian Yu
- & Hai-Bo Wang
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Article
| Open AccessGSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis
Macrophages have been shown to have an important function in atherosclerosis. Here the authors show that, in human atherosclerotic plaques and mouse models, GSDME and pyroptosis promote atherosclerosis and inhibition of these pathways could reduce pathology associated with atherosclerotic disease.
- Yuanyuan Wei
- , Beidi Lan
- & Yue Wu
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Article
| Open AccessA subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis
Although anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis and generally considered pathogenic, their functional relevance is incompletely understood. In this study, the authors describe an ACPA with a protective effect against antibody-induced arthritis in mice.
- Yibo He
- , Changrong Ge
- & Rikard Holmdahl
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Article
| Open AccessMicrobiota-derived acetate enhances host antiviral response via NLRP3
The NLRP3 inflammasome plays a pivotal role in clearing viral respiratory infection, but the molecular mechanism is not fully known. Here authors show that acetate, produced by gut bacteria, may enhance NLRP3-mediated type I interferon production following influenza infection in mice.
- Junling Niu
- , Mengmeng Cui
- & Guangxun Meng
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Article
| Open AccessCopper intrauterine device increases vaginal concentrations of inflammatory anaerobes and depletes lactobacilli compared to hormonal options in a randomized trial
Here, in a randomized trial, the authors comparatively evaluate the effect of a copper intrauterine device versus other contraceptive options on the vaginal environment after one and six consecutive months of use, finding to exert changes on the vaginal microbiota that may potentially lead to detrimental sex and reproductive health.
- Bryan P. Brown
- , Colin Feng
- & Heather B. Jaspan
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Article
| Open AccessLocally organised and activated Fth1hi neutrophils aggravate inflammation of acute lung injury in an IL-10-dependent manner
Acute respiratory distress syndrome (ARDS) is an acute pulmonary disease involving neutrophils. Here the authors characterise lung neutrophil infiltration during ARDS and show that there are neutrophils with different function and transcriptional profile which are regulated by IL-10.
- Kun Wang
- , Muyun Wang
- & Wei Gao
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Article
| Open AccessCD1a promotes systemic manifestations of skin inflammation
Skin inflammation is often accompanied by systemic disease, yet the pathways that regulate this escalation are little known. Here authors show that transgenic expression of human CD1a in mice leads to the escalation of experimental skin inflammation and systemic inflammatory disease, and the generalized symptoms could be alleviated by blocking antibodies developed against CD1a.
- Clare S. Hardman
- , Yi-Ling Chen
- & Graham S. Ogg
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Article
| Open AccessmTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome
Still’s disease is an inflammatory syndrome linked to the development of further immune dysregulation and hypercytokinaemia termed macrophage activation syndrome. Here the authors implicate the mechanistic target of rapamycin complex 1 in murine models of Still’s disease and macrophage activation syndrome, and provide associations with clinical cases in patients
- Zhengping Huang
- , Xiaomeng You
- & Pui Y. Lee
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Article
| Open AccessInflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer
Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.
- Qiaoqi Sui
- , Xi Zhang
- & Pei-Rong Ding
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Article
| Open AccessGPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages
G-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.
- Jing Yan
- , Yuemei Zhang
- & Cheng Hu
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Article
| Open AccessCXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD) is a life-threatening inflammatory disease requiring immediate intervention, for which the recommended first-line therapy is the Interleukin-6 pathway inhibitor siltuximab. Authors here show that the change in levels of the chemokine CXCL13 shortly following the start of siltuximab treatment is predictive of response.
- Sheila K. Pierson
- , Laura Katz
- & David C. Fajgenbaum
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Article
| Open AccessMutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling
By recognizing double-stranded RNA, RIG-I is implicated in anti-viral immune responses, but also in cancer development and intestinal inflammation. Here the authors identify frameshift germline mutations of RIG-I, resulting in the generation of a circular RNA associated with increased susceptibility to colitis-associated colon cancer.
- Jia Song
- , Wei Zhao
- & Dan Lu
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Article
| Open AccessNeutrophil breaching of the blood vessel pericyte layer during diapedesis requires mast cell-derived IL-17A
The blood vessel wall is a complex multi-layered structure, yet upon injury or infection, neutrophil leukocytes are rapidly migrating from the blood stream to the affected tissues, by a process termed diapedesis. Authors here show that the final steps of diapedesis through the outer pericyte layer is regulated by perivascular mast cells via IL-17A production.
- Régis Joulia
- , Idaira María Guerrero-Fonseca
- & Mathieu-Benoit Voisin
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Article
| Open AccessYAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro
Growing evidence indicates that YAP/TAZ transcriptional regulators promote autophagy. Here, the authors characterize the role of YAP against Staphyloccocus aureus infection of synovial organoids and describe the role staphylococcal toxins have in antagonizing YAP-mediated functions.
- Robin Caire
- , Estelle Audoux
- & Paul O. Verhoeven
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| Open AccessRasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth
IL-6 and RasGRP1 have been shown to have important functions during inflammation and cancer. Here the authors propose the protein and mRNA of RasGRP1 have opposing functions by promoting IL-6 mediated acute inflammation and inhibiting inflammation-associated cancer through mRNA and protein mechanisms respectively.
- Cong Wang
- , Xue Li
- & Songqing Tang
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Article
| Open AccessSevere Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.
- Manina M. Etter
- , Tomás A. Martins
- & Gregor Hutter
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Article
| Open AccessDusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction
Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts.
- Xiaohai Zhou
- , Chenyang Zhang
- & Jing-Wei Xiong
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Article
| Open AccessTyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of cell death pathways during embryogenesis and in infection/inflammation. Here authors show that tyrosine phosphorylation of RIPK1 by upstream kinases limits systemic inflammation and regulates haematopoietic homeostasis.
- Hailin Tu
- , Weihang Xiong
- & Xin Lin