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An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with unclear immune cell involvement. Here the authors generate a single cell transcriptomic dataset with 400k cells from the esophageal mucosa of active EoE patients, remission EoE patients, and healthy individuals to characterise esophageal cellular composition, phenotype and interaction in this disease.
- Jiarui Ding
- , John J. Garber
- & Ramnik J. Xavier
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Gasdermin 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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| Open Access
Comparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
Mast cells serve as sentinels for mucosal infection. This study shows how mast cells can differentially detect extracellular and invasive gut bacteria, and in response tune their cytokine production to signal different levels of danger.
- Christopher von Beek
- , Anna Fahlgren
- & Mikael E. Sellin
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Cebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish
Eosinophils are innate immune cells critical for protection from parasites, but their developmental origin remains under studied. Here they analyze development of eosinophils in zebrafish and find that eosinophilic lineage commitment and differentiation are regulated by the Cebp1-Cebpβ axis.
- Gaofei Li
- , Yicong Sun
- & Yiyue Zhang
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An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life
Neutrophils play critical roles in response to infection, and the limit of available neutrophils in neonates and young infants can impact responses to infections, including sepsis. Here the authors identify that the IL-10/DEL-1 axis is involved in emergency granulopoiesis in neonates and suggest a link to sepsis survival in early life.
- Eleni Vergadi
- , Ourania Kolliniati
- & Christos Tsatsanis
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Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death
Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.
- Fengxia Ma
- , Laxman Ghimire
- & Hongbo R. Luo
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Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
- Shuangshuang Yang
- , Jie Xu
- & Sai-Juan Chen
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| Open Access
Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis
Mast cells have been shown to be involved with rheumatoid arthritis, but the mechanisms are not clear. Here using mouse models and making association with human patients, the authors show mast cells have an important function in the pathogenesis of rheumatoid arthritis, involving regulation of T cell responses and release of mast cell mediators.
- Yunxuan Lei
- , Xin Guo
- & Guangjie Chen
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| Open Access
Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Difficulties can be encountered when translating research between cells from animals and humans because of gene expression differences. Here the authors perform an integrative transcriptomic analysis from human and mouse neutrophils and identify a core inflammation program shared across inflamed contexts.
- Nicolaj S. Hackert
- , Felix A. Radtke
- & Ricardo Grieshaber-Bouyer
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Article
| Open Access
Single 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
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A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils
Vaccines that specifically induce immunity against bacterial pathogens are required. Here the authors produce and characterize an intranasal liposomal vaccine against a peptide antigen from Streptococcus pyogenes and show that it induces a strong mucosal IgA response lasting for over one year, and that protection is dependent on cellular immunity mediated through IL-17, macrophages and neutrophils.
- Victoria Ozberk
- , Mehfuz Zaman
- & Manisha Pandey
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CREB1-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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Ontogenetically distinct neutrophils differ in function and transcriptional profile in zebrafish
Neutrophil ontogeny in zebrafish may be a continuum or consist of distinct lineages. Here the authors characterise neutrophils derived from rostral blood island and caudal haematopoietic tissue lineages and show differential gene expression and function in steady state and during wound healing.
- Juan P. García-López
- , Alexandre Grimaldi
- & Carmen G. Feijoo
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The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils
Neutrophil activation has been shown to rely on the pentose phosphate pathway (PPP) for NADPH generation and reactive oxygen species production. In this study, the authors identify a mechanism of neutrophil activation that is independent of the PPP but relies on the glycolytic enzyme pyruvate kinase M2 instead.
- Juliana Escher Toller-Kawahisa
- , Carlos Hiroji Hiroki
- & José Carlos Alves-Filho
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High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection
The ambient environmental temperature changes the extent or severity of a virus infection. Here the authors show that influenza and SARS-CoV-2 infection at higher temperatures promotes gut microbiota derived deoxycholic acid signalling which increases host resistance to infection.
- Minami Nagai
- , Miyu Moriyama
- & Takeshi Ichinohe
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Single cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils
Single cell sequencing can be used to better characterize immune cell progenitors. Here the authors characterize CLEC12Ahi pre-basophils downstream of pre-basophil and mast cell progenitors (pre-BMPs) but upstream of mature basophils and this population includes basophil progenitors (BaPs).
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Prenylcysteine oxidase 1 like protein is required for neutrophil bactericidal activities
Neutrophils play critical roles in the response to infection and their function relies on a range of intrinsic and extrinsic factors. Here the authors show a role for Pcyox1l and link this to metabolic pathways including prenylation and the neutrophil response to infection.
- Anastasiia Petenkova
- , Shelby A. Auger
- & Mihaela Gadjeva
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Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation
Severe COVID-19 is characterized by an accumulation of and functional changes in neutrophils. Using metabolomics, the authors demonstrate that neutrophils display a reduction in GAPDH activity in severe COVID-19 and that GAPDH inhibition promotes neutrophil extracellular trap formation.
- Yafeng Li
- , Jessica S. Hook
- & Michalis Agathocleous
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Cargo-free particles divert neutrophil-platelet aggregates to reduce thromboinflammation
Platelet-neutrophil aggregates are a hallmark of thromboinflamation. Here, the authors use cargo-free particles to block platelet-neutrophil aggregates’ vascular wall adhesion, which could become an effective thromboinflammation therapy, regardless of disease cause.
- Alison L. Banka
- , M. Valentina Guevara
- & Omolola Eniola-Adefeso
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Lung-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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Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus
Systemic lupus erythematosus is characterised by the generation of antibodies targeting DNA and nuclear antigens. Here, the authors show that oxidised mitochondrial DNA induces gasdermin D oligomerization and promotes pore formation in neutrophils from patients with SLE.
- Naijun Miao
- , Zhuning Wang
- & Jing Wang
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Locally 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 Access
Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system
Innate and adaptive immune cells function in the homeostasis of haematopoietic stem cells (HSC). Here the authors show that myeloid cells are able to reduce the function of HSCs via interferon signaling through a neutrophil-NK cell dependent process.
- Jacqueline Feyen
- , Zhen Ping
- & Marc H. G. P. Raaijmakers
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Neutrophil 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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PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow
Programmed death ligand 1 (PD-L1) suppresses host immunity during infection and microbial sepsis. Here, the authors show that PD-L1 does this by regulating the secretion of CXCL1 and CXCL2 to control neutrophil mobilization during Candida albicans infection.
- Yao Yu
- , Rong-Rong Wang
- & Xin-Ming Jia
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Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis
Hyperferritinemic syndrome is a collective term for a group of severe inflammatory conditions distinguished by high ferritin levels, including adult-onset Still’s disease and COVID-19. Here authors show in an animal model that high ferritin levels are not just a sign of hyperinflammation but also a pathogenic factor that triggers neutrophil leukocyte activation and extracellular trap formation.
- Jinchao Jia
- , Mengyan Wang
- & Qiongyi Hu
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GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation
Activation of neutrophil leukocytes is tightly regulated, and it is important to understand the molecular mechanisms of their response to physiological and pathological stimuli. Here authors show that the adhesion molecule G protein-coupled receptor 97 and its interaction partners play pivotal roles in neutrophil leukocyte activation both in anti-microbial response and in inflammatory diseases.
- Tai-Ying Chu
- , Céline Zheng-Gérard
- & Hsi-Hsien Lin
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Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
- Polychronis Pavlidis
- , Anastasia Tsakmaki
- & Nick Powell
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Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation
Responsive exocytosis in neutrophil leukocytes involves actin depolymerisation-dependent sequential release of gelatinase granules, then strongly pro-inflammatory azurophilic granules. Here authors show that the actin nucleator protein WASH facilitates the initial step of innate immune activation by gelatinase granules while inhibiting release of pro-inflammatory granules.
- Jennifer L. Johnson
- , Elsa Meneses-Salas
- & Sergio D. Catz
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| Open Access
Microbe capture by splenic macrophages triggers sepsis via T cell-death-dependent neutrophil lifespan shortening
Hyperinflammation and immune dysfunction are key drivers of immunopathology in sepsis. Here the authors show microbial exploitation of phagocytic receptors is linked to triggering of sepsis and the immune cell mediated reduction in neutrophil life span.
- Marianna Ioannou
- , Dennis Hoving
- & Venizelos Papayannopoulos
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Neutrophils restrain sepsis associated coagulopathy via extracellular vesicles carrying superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis
Disseminated intravascular coagulation is associated with sepsis and a number of inflammatory components have been linked to sepsis associated coagulopathy. Here the authors show neutrophils can prevent lethal coagulopathy via the production of extracellular vesicles that carry superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis.
- Wenjie Bao
- , Huayue Xing
- & Xiaolong Liu
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Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts
Cellular composition and function are not clearly defined in heart failure after myocardial infarction. Here, using single cell and spatial transcriptomics in a MI-HF mouse model, the authors show that macrophages expressing Trem2 are found within the infarcts and this could be a useful biomarker.
- Seung-Hyun Jung
- , Byung-Hee Hwang
- & Yeun-Jun Chung
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| Open Access
Minimally invasive detection of cancer using metabolic changes in tumor-associated natural killer cells with Oncoimmune probes
NK cells can be affected by tumour cells and this difference could be utilised as a cancer diagnostic. Here the authors use a nickel based plasmonic spectroscopy system to measure metabolic differences in NK cells that have been exposed to cancer cells as a method of cancer detection.
- Deeptha Ishwar
- , Rupa Haldavnekar
- & Bo Tan
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| Open Access
Airway Prevotella promote TLR2-dependent neutrophil activation and rapid clearance of Streptococcus pneumoniae from the lung
How the airway microbiome protects against bacterial pneumonia remains unclear. Here, the authors identify airway bacterial species that activate the immune system to facilitate rapid clearance of the pathogen Streptococcus pneumoniae from the lung.
- Kadi J. Horn
- , Melissa A. Schopper
- & Sarah E. Clark
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| Open Access
Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2
Neutrophils are critical in the immune response to infective agents and have multiple effector strategies including the production of extracellular traps termed NETs. Here the authors show a link between NET production and Th17 differentiation which mechanistically occurs downstream of TLR2 signalling.
- Alicia S. Wilson
- , Katrina L. Randall
- & Anne Brüstle
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| Open Access
The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model
Exposure at birth to maternal microbiota has significant effects on offspring health and development. Here, the authors validate a model where inoculation of mice at birth with human vaginal microbiota produces significant effects on offspring health that are further amplified by an unhealthy prenatal environment.
- Eldin Jašarević
- , Elizabeth M. Hill
- & Tracy L. Bale
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| Open Access
Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection
SARS-CoV-2 infection of expecting mothers has been reported. Here the authors profile the peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection to find grossly normal immune cell composition but heterogenous induction of pro-inflammatory cytokines, thereby implicating possible therapeutic targets for virus-induced damages during pregnancy.
- Sara De Biasi
- , Domenico Lo Tartaro
- & Andrea Cossarizza
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| Open Access
TcpC inhibits neutrophil extracellular trap formation by enhancing ubiquitination mediated degradation of peptidylarginine deiminase 4
TcpC is a well characterised multifunctional virulence factor expressed by uropathogenic Eschericia coli. Here the authors show that TcpC also targets neutrophil NETosis via its E3 ligase functionality promoting the degradation of PAD4, and represents an additional immune evasion function of this bacterially derived virulence factor.
- Qian Ou
- , Jia-qi Fang
- & Jian-ping Pan
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Article
| Open Access
A sand fly salivary protein acts as a neutrophil chemoattractant
Immune mimicry has been shown in chemokine like moieties from bacteria and viruses. Here, the authors characterise a sand fly salivary protein that induces neutrophil chemotaxis and explore its impact in a model of parasitic infection.
- Anderson B. Guimaraes-Costa
- , John P. Shannon
- & Fabiano Oliveira
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| Open Access
The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments
Differentiating neutrophil functional states is difficult. Here the authors show, using single cell RNA-sequencing and trajectory analyses, that mouse neutrophils can be presented as a transcriptome continuum rather than discrete subsets, but are affected by inflammation to express distinct transcriptional states.
- Ricardo Grieshaber-Bouyer
- , Felix A. Radtke
- & Hideyuki Yoshida
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| Open Access
Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer
Radioresistance remains a challenge in the treatment of bladder cancer. In this study, the authors show in mice that radiation increases deposits of neutrophil extracellular traps (NETs) via a TLR4-dependent mechanism and that NETs-targeting strategies can improve the response to radiotherapy.
- Surashri Shinde-Jadhav
- , Jose Joao Mansure
- & Wassim Kassouf
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| Open Access
The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation
Neutrophils secrete numerous immune effector molecules including cathelicidin which is associated with antimicrobial properties. Here the authors implicate neutrophil derived cathelicidin in modulation of CD4 T cell homoeostasis and the promotion of Th17 CD4 T cells.
- Danielle Minns
- , Katie J. Smith
- & Emily Gwyer Findlay
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| Open Access
Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth
The tumor microenvironment is composed of many cell types that crosstalk to modulate local immunity. Here the authors show that Amyloid β proteins from cancer-associated fibroblasts (CAF) induce neutrophil extracellular trap (NET) production by neutrophils, while NET feeds back to activate CAF, thereby implicating Amyloid β as a potential therapy target.
- Hafsa Munir
- , James O. Jones
- & Jacqueline D. Shields
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| Open Access
Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy
Immune checkpoint therapies (ICT) are promising for treating various cancers, but response rates vary. Here the authors show, in mouse models, that tumor-infiltrating mast cells colocalize with regulatory T cells, coincide with local reduction of MHC-I and CD8 T cells, and is associated with resistance to ICT, which can be reversed by c-kit inhibitor treatment.
- Rajasekharan Somasundaram
- , Thomas Connelly
- & Meenhard Herlyn
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| Open Access
Eosinophils improve cardiac function after myocardial infarction
Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation.
- Jing Liu
- , Chongzhe Yang
- & Guo-Ping Shi
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| Open Access
Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling
Lactate is a by-product of glycolysis that can function via its G protein receptor GPR81. Here the authors show that LPS or Salmonella infection enhances glycolytic metabolism in bone marrow neutrophils, resulting in lactate production, which increases endothelial barrier permeability and mobilization of these neutrophils by targeting endothelial GPR81.
- Eman Khatib-Massalha
- , Suditi Bhattacharya
- & Tsvee Lapidot
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| Open Access
Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis
Chemical tools to monitor drug-target engagement of endogenous enzymes are essential for preclinical target validation. Here, the authors present a chemical genetics strategy to study target engagement of endogenous kinases, achieving specific labeling and inactivation of FES kinase to provide insights into FES’ role in neutrophil phagocytosis.
- Tom van der Wel
- , Riet Hilhorst
- & Mario van der Stelt
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| Open Access
Eosinophil function in adipose tissue is regulated by Krüppel-like factor 3 (KLF3)
Immune cells are important regulators of adipose tissue function, including adaptive thermogenesis. Here the authors show that mice with Krüppel-like factor 3 (KLF3) deficiency in bone marrow-derived cells have increased adipose tissue beiging which may at least in part be due to altered eosinophil paracrine signaling.
- Alexander J. Knights
- , Emily J. Vohralik
- & Kate G. R. Quinlan
PD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus