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| Open AccessThe transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure
Acute hypoxemic respiratory failure (AHRF) and the associated lung immune cell features are not well understood. Here the authors use CITE-Seq to analyse the transcriptomic and phenotypic profile of lung and blood cells from a longitudinal cohort of patients with AHRF to identify gene signatures and cell surface proteins associated with disease severity.
- Eric D. Morrell
- , Sarah E. Holton
- & Carmen Mikacenic
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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 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 AccessFatty acid desaturation and lipoxygenase pathways support trained immunity
Cellular functional states are supported by metabolic pathways, including lipid metabolism. Here, authors examine the contribution of differential biosynthesis of lipid mediators to innate immune memory (or trained immunity), in human monocytes following Bacillus Calmette-Guérin (BCG) vaccination.
- Anaísa V. Ferreira
- , Juan Carlos Alarcon-Barrera
- & Martin Giera
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Article
| Open AccessMucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease
Mucosal associated invariant T (MAIT) cells reside in barrier organs, but their contribution to inflammatory processes in the kidneys is not fully known. Here authors find by single cell RNA sequencing that among the different MAIT cell subtypes found at steady state, a population with MAIT17 signature is expanded in both human crescentic glomerulonephritis and its mouse model, and these cells may play protective role in the disease.
- Ann-Christin Gnirck
- , Marie-Sophie Philipp
- & Jan-Eric Turner
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Article
| Open AccessDeciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution
The mechanism of parturition initiation remains elusive. Here, authors show that epithelium is an underestimated site for parturition initiation via epithelial PGF2a regulated by SHP2-COX1/COX2.
- Meng Liu
- , Mengjun Ji
- & Wenbo Deng
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Article
| Open AccessRNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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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 AccessMicroglia are not protective against cryptococcal meningitis
Cryptococcal meningitis is a life-threatening fungal infection. Here, Mohamed et al find that brain resident microglia do not provide protection against this infection and instead are a site where the fungus may access the micronutrient copper.
- Sally H. Mohamed
- , Man Shun Fu
- & Rebecca A. Drummond
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Article
| Open AccessThemis2 regulates natural killer cell memory function and formation
Innate immunity represents the first line of defence against pathogens, but certain innate cells are capable of memory formation, albeit with different and lesser-known mechanisms than adoptive immune cells. Here authors show that Themis2 regulates both memory NK cell development and function, via distinct downstream pathways.
- Tsukasa Nabekura
- , Elfira Amalia Deborah
- & Akira Shibuya
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Article
| Open AccessTissue-resident B cells orchestrate macrophage polarisation and function
The function of B cells in peripheral blood and secondary lymphoid organs has long been appreciated but whether and how they contribute to tissue immune homeostasis is lesser known. Non-lymphoid organs harbour tissue-resident B cells that include a substantial population of B-1 cells and promote homeostatic anti-inflammatory macrophage polarization via IL-10, with profound effects on bacterial clearance during local infection.
- Ondrej Suchanek
- , John R. Ferdinand
- & Menna R. Clatworthy
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Article
| Open AccessA tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development
Within gastrointestinal tissues, tuft cells, a rare population of chemo-sensory epithelial cells, can promote the activation of type 2 innate lymphoid cells (ILC2s). Here the authors show that tuft cells and ILC2s are increased during gastric cancer development and that the pharmacologic inhibition of tuft cell derived IL25 or ILC2-produced IL13 reduces gastric tumor growth.
- Ryan N. O’Keefe
- , Annalisa L. E. Carli
- & Michael Buchert
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Article
| Open AccessImmune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells
CD4+ T cells have been shown to be important in CD8+ T cell responses through a process of DC:T cell interaction. Here the authors further characterise this DC:T cell interaction and show that after CD4+ T cell help these post-synaptic DCs have increased lipid peroxidation and increased MHC class I proteins associated with increased cross-presentation function.
- Diego Calzada-Fraile
- , Salvador Iborra
- & Francisco Sánchez-Madrid
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Article
| Open AccessOrganoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization
Intestinal ischemia/reperfusion (I/R) injury is a life-threatening problem in surgeries. Here, authors report that intestinal organoids transplantation attenuates intestinal I/R injury in mice through L-Malic acid-mediated M2 macrophage polarization.
- Fang-Ling Zhang
- , Zhen Hu
- & Ke-Xuan Liu
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Article
| Open AccessThe transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells
Type 1 conventional dendritic cells (cDC1) play a pivotal role in the cross-presentation of antigens, enabling efficient CD8 + T cell response. Here authors show that the transcription factor Zeb1 essentially regulates this process via facilitating the reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytoplasm.
- Yan Wang
- , Quan Zhang
- & Nengming Xiao
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Article
| Open AccessPerinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
Early life infections are known to impact and modulate the immune response in later life. Here the authors show that perinatal infection with murine cytomegalovirus results in a modified transcriptional profile and functionality in murine NK cells.
- Carmen Rožmanić
- , Berislav Lisnić
- & Ilija Brizić
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Article
| Open AccessSUN1/2 controls macrophage polarization via modulating nuclear size and stiffness
Stiffness and size of the nucleus may affect the function of specific cell types. Here the authors show that LPS treatment of macrophages affects the nucleus stiffness and size involving nuclear envelope proteins SUN1/2, chromatin accessibility and M1 associated gene expression.
- Shi Jiao
- , Chuanchuan Li
- & Zhaocai Zhou
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Article
| Open AccessPolarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release
Microglia drastically change their morphology when reacting to pathological stimuli. Here, the authors study the molecular responses to stimulation and unravel cytoskeleton remodeling pathways that induce morphological and functional changes.
- Max Adrian
- , Martin Weber
- & Casper C. Hoogenraad
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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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 AccessMyo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic islet β cells. Here the author show, by comparing the diabetes-sensitive NOD mouse strain with its congenic, diabetes-resistant ALR strain, and by genomic analyses of T1D patients and control, that mutations in the Myo9b gene may alter dendritic cells to contribute to autoimmune diabetes onset.
- Jing Zhang
- , Yuan Zou
- & Cong-Yi Wang
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Article
| Open AccessA 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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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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Article
| Open AccessMetabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors
The functional-metabolic state of macrophages fundamentally influences the tumour microenvironment, making adoptive cell therapy with pro-inflammatory macrophages an attractive anti-tumour approach. Here authors introduce pluripotent stem cell-derived CAR-macrophage that are depleted of ACOD1, an essential gene in itaconate metabolism, which reprograms them to a pro-inflammatory state enabling enhanced anti-tumour function.
- Xudong Wang
- , Siyu Su
- & Jin Zhang
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Article
| Open AccessSolar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary–lung axis
Allergic asthma is episodic and associated with seasonal changes which may have links with UV exposure levels. Here the authors propose a link between UVB exposure and ILC2 function through α-MSH released from the pituitary gland which accumulates in the serum and alters ILC2 function through the MC5R receptor.
- Yuying Huang
- , Lin Zhu
- & Bing Sun
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| Open AccessMetabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection
Gauging the in vivo metabolism of immune cells at the single-cell level has proven challenging. Here the authors use spectral flow cytometry to investigate metabolic profiles in tissue-resident macrophages from several organs and changes in response to helminth infection.
- Graham A. Heieis
- , Thiago A. Patente
- & Bart Everts
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Article
| Open AccessOptogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy
Optogenetics makes use of light-sensitive proteins to control biological processes using light. Here, the authors present an optogenetic system that regulates the cGAS/STING pathway remotely and demonstrate its efficacy in murine tumour models.
- Yaling Dou
- , Rui Chen
- & Yun Huang
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Article
| Open AccessAntibody-mediated NK cell activation as a correlate of immunity against influenza infection
Antibodies play a crucial role in protection from influenza virus infection, but functional details, particularly in older adults, are incomplete. Here the authors show that NK cell-activating antibodies are associated with protection from influenza infection in vaccinated older adults.
- Carolyn M. Boudreau
- , John S. Burke IV
- & Galit Alter
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Article
| Open AccessMetabolic glycan labeling immobilizes dendritic cell membrane and enhances antitumor efficacy of dendritic cell vaccine
Dendritic cell (DC) vaccines were among the first FDA-approved cancer immunotherapies but have been limited by the modest therapeutic efficacy. Here, authors report a facile metabolic glycan labeling approach to improving the cytotoxic T lymphocyte response and antitumor efficacy of DC vaccines.
- Joonsu Han
- , Rimsha Bhatta
- & Hua Wang
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Article
| Open AccessOntogenetically 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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Article
| 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 AccessGenetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy
Previous studies suggested a role for CARD9 pathway in atherosclerosis but the underlying mechanisms remain poorly understood. Here, the authors show that the pro-atherogenic effects of Card9 deficiency are mediated by CD36-dependent defective autophagy that can be reversed by rapamycin and metformin.
- Yujiao Zhang
- , Marie Vandestienne
- & Hafid Ait-Oufella
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Article
| Open AccessEzh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.
- Julie Rondeaux
- , Déborah Groussard
- & Sylvain Fraineau
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Article
| Open AccessThe 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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Article
| Open AccessInterventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy
Minimally invasive irreversible electroporation shows some therapeutic promise in irresectable pancreatic cancers that are notorious for poor survival. Here authors combine this with administration of a hydrogel microsphere vaccine that augments the antigen presentation T cell response cascade that naturally initiates following ablation.
- Xiaoyu Liu
- , Yaping Zhuang
- & Zhongmin Wang
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Article
| Open AccessMacrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model
Migrasomes are recently discovered extracellular vesicles that are produced during cellular migration. Here, the authors show that macrophage-derived migrasomes are implicated in the progression of cerebral amyloid angiopathy (CAA) through increased complement signaling using skin biopsies from CAA patients and CAA mouse models.
- Mengyan Hu
- , Tiemei Li
- & Wei Cai
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Article
| Open AccessHigh 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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Article
| Open AccessSelective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis
Ulcerative colitis is associated with increased infiltration and cellularity, yet the precise tissue topology remains poorly understood. Here the authors employ imaging mass cytometry and single-cell RNA sequencing to characterise intestinal lesions in patients with ulcerative colitis, and show the architecture at the individual cell level which includes a decrease in the resident macrophage population.
- Juan Du
- , Junlei Zhang
- & Jianpeng Sheng
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Article
| Open AccessTnpo3 controls splicing of the pre-mRNA encoding the canonical TCR α chain of iNKT cells
iNKT cells recognise glycolipids via their T cell receptors. Here the authors implicate tnpo3 in the regulation of splicing of pre-mRNA encoding cognate TCR α chain for iNKT cells.
- Norimasa Iwanami
- , Andreas S. Richter
- & Thomas Boehm
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Article
| 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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Article
| 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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Article
| Open AccessA smart pathogen detector engineered from intracellular hydrogelation of DNA-decorated macrophages
Macrophages have the inherent capacity to recognise pathogenic microorganisms, highlighting their potential to be used in biosensing applications. Herein, the authors report a method to transform normally fragile macrophages into robust gelated cell particles for efficient bacterial capture and detection.
- Yueyue Gui
- , Yujing Zeng
- & Chao Li
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Article
| Open AccessPlatelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles
Skeletal muscle has a remarkable capacity to regenerate in response to injury, but it is not entirely understood how this regeneration initiates. Here, Graca et al. show that platelet-secreted chemokines promote the early steps of muscle regeneration by recruiting neutrophils to injured muscles.
- Flavia A. Graca
- , Anna Stephan
- & Myriam Labelle
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Article
| Open AccessSingle 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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Article
| Open AccessPrenylcysteine 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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Article
| Open AccessNeutrophil 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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Article
| Open AccessCargo-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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Article
| 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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Article
| Open AccessTargeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
Chemotherapy priming sensitizes triple-negative breast cancers to immune checkpoint blockade. However, immune suppressive myeloid cells may impede its optimal effect. Here authors characterise the immune suppressive myeloid cells via single-cell analyses of immune cells from low dose chemotherapy treated breast tumours and identify STAT1 signalling as a regulator for immune suppressive state.
- Bhavana Palakurthi
- , Shaneann R. Fross
- & Siyuan Zhang