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| Open AccessGPR97 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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Article
| Open AccessMetabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion
Chemo-resistance and immune evasion are major challenges in osteosarcoma treatment. Here the authors show that doxorubicin promotes IL-18 secretion by tumor associated macrophages inducing LAT2-dependent CD47 upregulation in osteosarcoma cells, suggesting LAT2 inhibition as a therapeutic option in combination with doxorubicin.
- Zenan Wang
- , Binghao Li
- & Zhaoming Ye
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Article
| Open AccessBlood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma
Tumor-associated macrophages are believed to promote tumour progression and to hamper immune therapy in gliomas. Here authors identify a distinct population of macrophages within the glioblastoma immune microenvironment with antitumour properties and clearly distinguishable phenotypes and gene expression patterns from tumour promoting macrophages.
- Hyun-Jin Kim
- , Jang Hyun Park
- & Heung Kyu Lee
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Article
| Open AccessInterleukin-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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Article
| Open AccessInterferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection
Innate lymphoid cells (ILC) are involved with different immune responses. Here the authors show that Interferon regulatory factor 1 (IRF1) is important for intestinal ILC3 accumulation during Citrobacter rodentium infection and promotes release of the protective cytokine IL-22 and response to IL-23.
- Angelika Schmalzl
- , Tamara Leupold
- & Stefan Wirtz
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Article
| Open AccessDifferential 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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Article
| Open AccessAn anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in zebrafish
Macrophages are important for tissue regeneration after injury. Here, using a single cell sequencing approach in a zebrafish injury model, the authors show that macrophages transition through a three stage process during tissue regeneration after hair cell damage.
- Nicolas Denans
- , Nhung T. T. Tran
- & Tatjana Piotrowski
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Article
| Open AccessLiver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka
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Article
| Open AccessCancer co-opts differentiation of B-cell precursors into macrophage-like cells
The tumour microenvironment has been shown to change the phenotypes and functionality of immune cells to enable tumour propagation. Here authors show that cancers can derail B cell development to give rise to macrophage-like cells, contributing to cancer progression and metastasis via disabling local T cell response.
- Chen Chen
- , Bongsoo Park
- & Arya Biragyn
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Article
| Open AccessSREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus
Zika virus (ZIKV) infection suppresses the induction of dendritic cell (DC)-derived immunity, but the underlying mechanistical insights are still lacking. Here the authors show, using in vitro systems profiling of DC transcriptome and epigenome, that ZIKV specifically alters SREBP2-related expression of inflammation- and metabolism-related genes to modulate DC functions.
- Emilie Branche
- , Ying-Ting Wang
- & Aaron F. Carlin
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Article
| Open AccessAdipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. The authors show that adipocytes release lactate as a signal of inflammation and that this metabolite can enhance obesity associated inflammation through stimulation of ATM by direct binding with PHD2.
- Tianshi Feng
- , Xuemei Zhao
- & Xiaoyan Hui
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Article
| Open AccessTranscription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes
The transcription factor IRF8 has been shown to regulate monocyte differentiation via its DNA-binding activity. Here authors show that IRF8 is also involved in cytosolic DNA sensing via its phosphorylation-dependent association to the adaptor protein STING, thus representing an important checkpoint between immune response and autoimmunity in monocytes.
- Wei-Wei Luo
- , Zhen Tong
- & Yan-Yi Wang
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Article
| Open AccessCircular RNA circTmem241 drives group III innate lymphoid cell differentiation via initiation of Elk3 transcription
Innate lymphoid cells (ILC) have been shown to be involved in a range of inflammatory contexts but how their cellular lineage is regulated is not fully established. Here the authors show a role for circular RNA circTmem241 in the differentiation of ILC3 via initiation of Elk3 transcription.
- Nian Liu
- , Jiacheng He
- & Zusen Fan
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Article
| Open AccessMicrobe 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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Article
| Open AccessSpatiotemporal 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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Article
| Open AccessNeutrophils 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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Article
| Open AccessA single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma
The immune cell constituents and localisation within human hepatocellular carcinoma is not fully understood. Here the authors use single cell RNA sequencing of HCC from four different tissue sites and show differences between primary and metastatic tumours, tumour associated macrophages and immune cell populations.
- Yiming Lu
- , Aiqing Yang
- & Gangqiao Zhou
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Article
| Open AccessPregnancy-induced maternal microchimerism shapes neurodevelopment and behavior in mice
During pregnancy, maternal cells are transferred to the fetus, where they can reach the developing brain. In this study, the authors demonstrate that these maternal cells play an important role in neurodevelopment.
- Steven Schepanski
- , Mattia Chini
- & Petra C. Arck
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Article
| Open AccessMinimally 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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Article
| Open AccessCancer immune therapy using engineered ‛tail-flipping’ nanoliposomes targeting alternatively activated macrophages
Tumor-associated macrophages are mostly pro-tumorigenic, due to their re-programming by the tumor microenvironment. Here authors show that nanoliposomes, incorporating phospholipids with a flipping-tail chain, are engulfed specifically by intratumoral, alternatively activated macrophages, while delivering a cargo that converts these cells into anti-tumor macrophages.
- Praneeth R. Kuninty
- , Karin Binnemars-Postma
- & Jai Prakash
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Article
| Open AccessIn mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response
The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
- Juliane Glaubitz
- , Anika Wilden
- & Matthias Sendler
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Article
| Open AccessRNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R
The function of RNA binding proteins within innate lymphoid cells (ILC) has been partially characterised. Here the authors show that RBM3 functions to limit the type 2 immunity promoting activity of ILC2 partially through cysteinyl leukotriene 1 receptor.
- Jana H. Badrani
- , Allyssa N. Strohm
- & Taylor A. Doherty
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Article
| Open AccessMouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade
Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction.
- Gurman Kaur
- , Caroline B. M. Porter
- & Lars Fugger
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Article
| Open AccessPathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling
Guanylate-binding proteins (GBP) have a function in inflammasome formation and pathogen defence. Here the authors show that these GBP proteins are able to kill certain bacteria and promote selective inflammasome activation and that this is mediated by specific GBP protein regions.
- Shouya Feng
- , Daniel Enosi Tuipulotu
- & Si Ming Man
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Article
| Open AccessGata6+ resident peritoneal macrophages promote the growth of liver metastasis
GLPMs represent a population of fetal liver derived large peritoneal cavity Gata6+ macrophages, with the capacity to invade the tissues they surround. Here, in experimental colon cancer liver metastasis models, the authors show that GLPMs invade liver metastasis directly from the peritoneum, promoting liver metastases growth.
- Mokarram Hossain
- , Raymond Shim
- & Paul Kubes
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Article
| Open AccessNotch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation
Innate lymphoid cells (ILC) are effector cells that rapidly respond to immune evading stimuli, and despite their functional diversity arise from common precursors. Authors here show how the Notch signalling pathway orchestrates ILC development from circulating human ILC precursors via RORC and its target IL-23R.
- Carys A. Croft
- , Anna Thaller
- & James P. Di Santo
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Article
| Open AccessPostmitotic differentiation of human monocytes requires cohesin-structured chromatin
How chromatin structure and gene accessibility changes during monocyte differentiation is not clearly defined. Here the authors characterize the chromatin changes during macrophage or dendritic cell maturation from monocytes and the dependence of this upon cohesin and CTCF.
- Julia Minderjahn
- , Alexander Fischer
- & Michael Rehli
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Article
| Open AccessCalcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice
Calcium/calmodulin-dependent protein kinase IV (CaMK4) has been shown to be involved in autoimmunity but it is not clear how it functions in psoriasis. Here the authors show that CaMK4 is increased in psoriasis and promotes inflammatory responses in mouse models of psoriasis mediated through macrophages and keratinocytes.
- Liang Yong
- , Yafen Yu
- & Liangdan Sun
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Article
| Open AccessInhibition of myeloid-derived suppressor cell arginase-1 production enhances T-cell-based immunotherapy against Cryptococcus neoformans infection
Cryptococcus neoformans causes opportunistic infection and potentially lethal immunopathology but therapeutic options are limited. Here the authors implicate myeloid derived suppressor cells during C. neoformans infection and suggest targeting arginase-1 production as a potential therapeutic strategy.
- Ya-Nan Li
- , Zhong-Wei Wang
- & Xin-Ming Jia
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Article
| Open AccessCigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells
Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
- Jongho Ham
- , Jihyun Kim
- & Hye Young Kim
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Article
| Open AccessMouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9
The role of IL-9 in the tumor microenvironment and its effects on macrophages remains unclear. Here, the authors show that IL-9 promotes the expansion of pulmonary macrophages and that targeting the IL-9R/arginase 1 axis restricts tumor growth, thus identifying this cytokine pathway as a potential therapeutic target.
- Yongyao Fu
- , Abigail Pajulas
- & Mark H. Kaplan
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Article
| Open AccessKir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters
Potassium channels and membrane potential may influence macrophage function during inflammation. Here the authors show that the Kir2.1 potassium channel affects macrophage metabolism by altering cell surface retention of nutrient transporters and subsequently regulates inflammatory disease responses.
- Weiwei Yu
- , Zhen Wang
- & Di Wang
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Article
| Open AccessLy6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage
The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.
- Konstantin Lutz
- , Andrea Musumeci
- & Anne B. Krug
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Article
| Open AccessAirway 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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Article
| Open AccessEfferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity
Efficient removal of apoptotic cells by phagocytosis underlies tissue development, wound repair, host defense and organ homeostasis. Here, authors identify TRPM7 as a regulator of cargo acidification and Ca2+ signaling during apoptotic cell clearance.
- Michael S. Schappe
- , Marta E. Stremska
- & Bimal N. Desai
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Article
| Open AccessTargeting parvalbumin promotes M2 macrophage polarization and energy expenditure in mice
Exercise increases energy expenditure and suppresses obesity, but the effector mechanisms are not still unclear. Here the authors profile serum proteomics in exercised mice to find reduced parvalbumin levels that correlate with increased M2 macrophage and suppressed diet-induced obesity to hint parvalbumin as a potential therapy target against obesity.
- Shaojian Lin
- , Anke Zhang
- & Bing Luan
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Article
| Open AccessRe-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity
Invariant natural killer T (iNKT) cells are tissue-resident immune cells recognizing lipid antigens. Here the authors find that liver, but not lung nor spleen, iNKT cells alter their transcriptome upon systemic treatment of lipid nanoparticles for the induction of regulatory B cells and suppression of liver and pancreas autoimmunity in mouse models.
- Channakeshava Sokke Umeshappa
- , Patricia Solé
- & Pere Santamaria
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Article
| Open AccessMacrophages disseminate pathogen associated molecular patterns through the direct extracellular release of the soluble content of their phagolysosomes
The detection of conserved motifs by pattern recognition receptors is a crucial component of the innate detection of pathogens and danger signals via conserved pattern recognition receptors. Here the authors define a pathway that transfers partially digested material from the phagolysosomal pathway of macrophages to release at the plasma membrane which is associated with enhanced inflammatory potential, by a process they introduce as eructophagy.
- Catherine J. Greene
- , Jenny A. Nguyen
- & Robin M. Yates
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Article
| Open AccessDifferential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model
Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.
- Qizhou Lian
- , Kui Zhang
- & Huanhuan Joyce Chen
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Article
| Open AccessIntestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function
Fibroblastic reticular cells (FRCs) support localisation of immune cells in secondary lymphoid tissues but less is known about the lamina propria. Here the authors use scRNA-seq and intestinal infection to characterise FRCs in the intestinal lamina propria and show specialised niches that foster innate lymphoid cells during homeostasis and infection.
- Hung-Wei Cheng
- , Urs Mörbe
- & Burkhard Ludewig
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Article
| Open AccessPD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity
Phenotypic and functional states of dendritic cells critically influence the outcome of cancer and inflammation. Authors here show by single cell transcriptomics and in vitro validation assays that dichotomous PD-L1 and ICOSL expression assign dendritic cells to secretory and helper functions, with respective predominance of inflammatory cytokine expression or T helper cytokine induction.
- Caroline Hoffmann
- , Floriane Noel
- & Vassili Soumelis
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Article
| Open AccessUbiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86
Regulated trafficking of major histocompatibility complex class II and CD86 is a prerequisite of antigen presenting cell functionality. Authors show here that ubiquitin-like protein 3 is critically involved in the ubiquitination process that controls trafficking, with wide-ranging immunological consequences.
- Haiyin Liu
- , Kayla R. Wilson
- & Justine D. Mintern
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Article
| Open AccessCHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Genetic alteration can render tumor cells resistant to immune cell-mediated killing. Here based on a genome-wide CRISPR screening, the authors show that expression of CHMP2A confers tumor cell resistance to NK cell-mediated cytotoxicity, mechanistically involving CHMP2A-dependent regulation of extracellular vesicle secretion.
- Davide Bernareggi
- , Qi Xie
- & Dan S. Kaufman
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Article
| Open AccessLung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection
Smallpox is a highly contagious respiratory pathogen associated with a high mortality rate. Here the authors utilize a mouse model of intranasal vaccinia virus infection and show a C7 gene encoded virulence factor attenuates type I IFN release by lung type II alveolar epithelial cells and reduces lung inflammatory monocyte responses.
- Ning Yang
- , Joseph M. Luna
- & Liang Deng
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Article
| Open AccessThe arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD
Chronic obstructive pulmonary disease is a progressive and incurable chronic condition that involves accumulation of inflammatory macrophages in the lung tissue. Authors here show in mouse models of lung disease that PRMT7, a protein arginine methyltransferase, is an important regulator of recruitment and the pro-inflammatory phenotype of macrophages.
- Gizem Günes Günsel
- , Thomas M. Conlon
- & Ali Önder Yildirim
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Article
| Open AccessStroke induces disease-specific myeloid cells in the brain parenchyma and pia
How ischaemic stroke affects the brain borders is not fully understood. Here the authors show that a stroke-associated myeloid cell population occurs exclusively in brain parenchyma that shares features with neurodegenerative microglia and blockade of proteins on these cells can ameliorate stroke symptoms.
- Carolin Beuker
- , David Schafflick
- & Jens Minnerup
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Article
| Open AccessTLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy
The immunopathology of Duchenne Muscular Dystrophy includes a disturbed balance of pro and anti-inflammatory macrophages. Here the authors implicate trained innate immunity in a murine model of the disease, and reveal TLR4 as a key regulator of this process.
- Salyan Bhattarai
- , Qian Li
- & Basil J. Petrof
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Article
| Open AccessGlutaredoxin 1 controls monocyte reprogramming during nutrient stress and protects mice against obesity and atherosclerosis in a sex-specific manner
High-calorie diet promotes thiol oxidative stress and the reprogramming of blood monocytes, giving rise to obesogenic and proatherogenic macrophages. Here the authors report that loss of monocytic thiol transferase glutaredoxin 1 results in the derepression of sex-specific oxidative stress responses in macrophages, promoting atherogenesis and obesity in female mice.
- Yong Joo Ahn
- , Luxi Wang
- & Reto Asmis
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Article
| Open AccessThe induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression
The advent of immunotherapy has revolutionised cancer therapeutics, but its application in the context of pancreatic ductal adenocarcinoma has been limited. Here authors explore the effect of innate trained responses to fungal β-glucan and assess its effect in a murine model of pancreatic ductal adenocarcinoma where they observe reduced tumour burden and enhanced survival.
- Anne E. Geller
- , Rejeena Shrestha
- & Jun Yan