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| 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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| 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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| 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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| 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
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| Open AccessAccumulation of microbial DNAs promotes to islet inflammation and β cell abnormalities in obesity in mice
Obesity is associated with increased gut permeability, and microbial products that are leaked from the gut may contribute towards obesity-associated inflammation. Here the authors show that the leakage of gut extracellular vesicles containing microbial DNA leads to bacterial DNA accumulation in pancreatic β-cells, promoting obesity-associated islet inflammation.
- Hong Gao
- , Zhenlong Luo
- & Wei Ying
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Article
| Open AccessDivalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models
Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.
- Wei Qiao
- , Dayu Pan
- & Xu Cao
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Article
| Open AccessC-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis
The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis.
- Inhye Park
- , Michael E. Goddard
- & Claudia Monaco
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| Open AccessOxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Oxylipins are lipid mediators generated during infection for regulating inflammatory responses, but how they are removed is not completely clear. Here the authors show that cellular oxylipin removal is linked to mitochondria β-oxidation by CPT1, a mitochondria lipid importer protein, to serve as a metabolic checkpoint for oxylipin homeostasis and inflammation.
- Mariya Misheva
- , Konstantinos Kotzamanis
- & Valerie B. O’Donnell
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| Open AccessCRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease
CRIg is expressed on liver macrophages and binds Gram-positive bacteria to mediate phagocytosis, but it is not clear how its phagocytic functions contribute to liver homeostasis or disease. Here the authors report that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of alcoholic liver disease.
- Yi Duan
- , Huikuan Chu
- & Bernd Schnabl
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Article
| Open AccessAcetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming
Lactic acidosis is a metabolic state that occurs in injured tissues. Here the authors show that macrophages, in order to remain functional in acidosis, reduce their mitochondrial mass by mitophagy and rely on autophagy for survival, with mitochondrial integrity retained using acetoacetate as alternative fuel.
- Clément Adam
- , Léa Paolini
- & Pascale Jeannin
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| Open AccessDefactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation
The transcription factor, IRF5, has been implicated in the regulation of inflammation, but how IRF5 protein is activated is still unclear. Here the authors use inhibitor library screening, biochemical analyses and in vivo/ex vivo data to show that a protein tyrosine kinase, Pyk2, may be key for the activation of IRF5 in macrophages and inflammatory responses in the gut.
- Grigory Ryzhakov
- , Hannah Almuttaqi
- & Irina A. Udalova
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| Open AccessEpigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
Muco-obstructive lung diseases are characterised by airway macrophage (AM) populations which may have epigenetic changes. Here using a mouse model the authors show epigenetic alteration of AMs with changes in LPS response, phagocytosis and efferocytosis similar to culture with mucus in vitro.
- Joschka Hey
- , Michelle Paulsen
- & Marcus A. Mall
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| Open AccessAntibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus
Antibiotic resistance in Staphylococcus aureus is associated with reduced neutrophil recruitment. Here, Payne et al. link formylated peptides, which act as chemoattractants for neutrophils, with the antibiotic vancomycin and show that these hybrid compounds improve clearance of S. aureus by neutrophils.
- Jennifer A. E. Payne
- , Julien Tailhades
- & Max J. Cryle
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| Open AccessSpatiotemporal proteomic profiling of the pro-inflammatory response to lipopolysaccharide in the THP-1 human leukaemia cell line
“Protein relocalisation plays a major role in the innate immune response but remains incompletely characterised. Here, the authors combine temporal proteomics with LOPIT, a spatial proteomic workflow, in a fully Bayesian framework to elucidate spatiotemporal proteomic changes during the LPS-induced immune response in THP-1 cells.
- Claire M. Mulvey
- , Lisa M. Breckels
- & Kathryn S. Lilley
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| Open AccessSingle-cell RNA sequencing of peripheral blood mononuclear cells from acute Kawasaki disease patients
Immune cell changes are associated with Kawasaki disease (KD) pathogenesis. Here, using single cell RNA sequencing of PBMC, the authors show monocyte inflammatory genes are over-expressed in KD and TCR and BCR clonotype sequences show oligoclonal expansions after intravenous immunoglobulin therapy.
- Zhen Wang
- , Lijian Xie
- & Min Huang
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| Open AccessBrown adipose tissue monocytes support tissue expansion
Adipose tissue is composed of a number of adipocytes and a number of other cells including immune cells. Here the authors use single-cell sequencing of murine brown adipose tissue immune cells and describe multiple macrophage and monocyte subsets and show that monocytes contribute to brown adipose tissue expansion.
- Alexandre Gallerand
- , Marion I. Stunault
- & Stoyan Ivanov
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| Open AccessOffspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life
Influenza infection during pregnancy can affect health of offspring but it is not clear how this affects immune responses. Here the authors use a mouse model to show that influenza infection during pregnancy can increase susceptibility to secondary infection and alter immune cell function in offspring.
- Henning Jacobsen
- , Kerstin Walendy-Gnirß
- & Gülsah Gabriel
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Article
| Open AccessThe structural dynamics of macropinosome formation and PI3-kinase-mediated sealing revealed by lattice light sheet microscopy
Macropinocytosis is a cellular process for the uptake of extracellular fluid. Here, the authors use lattice light sheet microscopy to examine the spatial dynamics of the plasma membrane, PI3K activity, and structural differences of various macrophage cell types during macropinocytosis.
- Shayne E. Quinn
- , Lu Huang
- & Brandon L. Scott
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| Open AccessChloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis
The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.
- Lindsey Mayes-Hopfinger
- , Aura Enache
- & Emad S. Alnemri
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| Open AccessSingle-cell transcriptome of bronchoalveolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets
A longitudinal analysis of SARS-CoV-2 infection in humans is challenging. Here the authors show a single cell RNA-sequencing analysis of BAL fluid cells from ferrets and characterise the time dependent recruitment of macrophage subsets to the lungs in response to SARS-CoV-2 infection.
- Jeong Seok Lee
- , June-Young Koh
- & Su-Hyung Park
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| Open AccessRole of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels
Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1+ macrophage function and post-prandial cholesterol transport.
- M. S. Magalhaes
- , P. Smith
- & C. Bénézech
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| Open AccessLoss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization
The role of common fragile site associated genes such as FATS in the immune system is unclear. Here the authors show that deletion of Fats in a mouse tumour model leads to reduced tumour growth and change of macrophage phenotype from an M2-like to M1-like function.
- Lijuan Zhang
- , Kai Zhang
- & Rongxin Zhang
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| Open AccessInflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients
Pre-engraftment syndrome is a major consideration during clinical application of unrelated cord blood transfusion and monocytes represent a critical cell type in immune-pathogenesis. Here the authors further establish the role of monocytes and GM-CSF in pre-engraftment syndrome and show clinical administration of tocilizumab limits pathology in pre-engraftment syndrome pathology in patients.
- Linlin Jin
- , Zimin Sun
- & Haiming Wei
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Article
| Open AccessThe RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response
Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.
- Bo Liu
- , Jiancheng Huang
- & Cliff Y. Yang
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Article
| Open AccessNuclear ADP-ribosylation drives IFNγ-dependent STAT1α enhancer formation in macrophages
STAT1a is required for pro-inflammatory responses in macrophages. Here the authors reveal that post-translational modification of STAT1a, ADPribosylation, plays a critical role in enhancer formation and activation, thus modulating IFNγ-stimulated inflammatory responses in macrophages.
- Rebecca Gupte
- , Tulip Nandu
- & W. Lee Kraus
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| Open AccessMechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing
Macrophages perform diverse functions during immune responses, but the molecular mechanisms by which physical properties of the tissue regulate macrophage behavior remain unknown. Here the authors find that Piezo1 is a mechanosensor of stiffness, and that its activity modulates macrophage polarization responses.
- Hamza Atcha
- , Amit Jairaman
- & Wendy F. Liu
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| Open AccessTNF controls a speed-accuracy tradeoff in the cell death decision to restrict viral spread
Controlled cell death can be an efficient anti-viral strategy, but also leads to tissue damage and needs to be balanced. Oyler-Yaniv et al. combine mathematical modelling and microscopy to show that exposure to TNF in response to viral infection causes cells to tune their speed-vs-accuracy trade-off in cell death decision to limit HSV-1 spread.
- Jennifer Oyler-Yaniv
- , Alon Oyler-Yaniv
- & Roy Wollman
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| Open AccessGenetic fate-mapping reveals surface accumulation but not deep organ invasion of pleural and peritoneal cavity macrophages following injury
Body cavity macrophages reside on the serous surfaces of organs and believed to participate in organ repair following injury. Here the authors show with a fate-mapping reporter system that these cells, although accumulate at the surfaces of injured liver or lung, don’t penetrate deeply into the tissue.
- Hengwei Jin
- , Kuo Liu
- & Bin Zhou
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| Open AccessTREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation
Mycobacterial cell wall lipids can drive immunoevasion, but underlying mechanisms are incompletely understood. Here the authors show TREM2 is a pattern recognition receptor that binds non-glycosylated mycolic acid-containing lipids and inhibits Mincle-induced anti-mycobacterial macrophage responses.
- Ei’ichi Iizasa
- , Yasushi Chuma
- & Hiromitsu Hara
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| Open AccessCell barrier function of resident peritoneal macrophages in post-operative adhesions
Peritoneal adhesions are a major cause of complications after abdominal surgery. Here the authors use a post-operative abdominal adhesion model in mice to show that resident F4/80HighCD206− macrophages form a protective barrier that can be enhanced by IL-4 administration or adoptive transfer of these cells.
- Tomoya Ito
- , Yusuke Shintani
- & Ken Suzuki
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| Open AccessTargeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis
Celastrol might be useful in treating rheumatoid arthritis in part by inhibiting apoptosis of macrophages; however, systemic toxicity is a concern. Here the authors design celastrol-loaded nanoparticles that release a payload in response to MMP9 cleavage and show these NPs are effective at inducing apoptosis of human macrophages in vitro and a therapeutic effect with an adjuvant-induced arthritis model in rats.
- Caifeng Deng
- , Quan Zhang
- & Zhirong Zhang
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Article
| Open AccessMonocyte progenitors give rise to multinucleated giant cells
Multinucleated giant cells characterize granuloma formation in mycobacterial infections. Here the authors identify monocyte precursors with distinct immunological and metabolic properties as a source of the granuloma multinucleated giant cell compartment.
- Anne Kathrin Lösslein
- , Florens Lohrmann
- & Philipp Henneke
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| Open AccessCardiac macrophages prevent sudden death during heart stress
Cardiac immune cells play various roles in the maintenance of homeostasis and diseases in the heart. Here the authors show that cardiac resident macrophages are a critical regulator of cardiac impulse conduction through amphiregulin production, contributing to the prevention of sudden death.
- Junichi Sugita
- , Katsuhito Fujiu
- & Issei Komuro
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| Open AccessRecruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells
The peritoneal cavity is a complicated myeloid niche containing a mixed population of resident macrophages and infiltrating cells that are responsive to inflammatory cues. Here the authors trace the fate of these infiltrating macrophages, their conversion to resident cells and how this is altered by the local inflammatory state over time.
- P. A. Louwe
- , L. Badiola Gomez
- & S. J. Jenkins
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| Open AccessN6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA
N6-methyladenosine (m6A) RNA modification regulates RNA metabolism, and has been implicated in immune regulation. Here, the authors show that the m6A methyltransferase, METTL3, translocates into the cytoplasm to increase viral RNA m6A modification, decreases viral ds RNA content, and thereby dampens the RIG/MDA5-induced anti-viral immunity.
- Weinan Qiu
- , Qingyang Zhang
- & Pengyuan Yang
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Article
| Open AccessMitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages
IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.
- Jennifer K. Dowling
- , Remsha Afzal
- & Claire E. McCoy
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Article
| Open AccessFructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation
Myeloid cells are able to utilize a variety of monosaccharides from our diet, including fructose. Here the authors show that when monocytes are reliant on fructose as a carbon energy source they are reprogrammed towards oxidative metabolism, glutamine anaplerosis and a pro-inflammatory phenotype owing to excess pro-inflammatory cytokine production.
- Nicholas Jones
- , Julianna Blagih
- & Catherine A. Thornton
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Article
| Open AccessHigh-throughput phenotypic screen and transcriptional analysis identify new compounds and targets for macrophage reprogramming
Macrophages may polarize into different states with distinct regulatory functions for inflammation. Here the authors perform high-throughput in vitro screening of a library of ~4000 compounds to identify those with specific effects on human macrophage polarization, while RNAseq helps uncover the targets and pathways mediating these effects.
- Guangan Hu
- , Yang Su
- & Jianzhu Chen
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Article
| Open AccessTargeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis
RAGE signalling is implicated in sepsis. Here the authors use T7 phage display to identify SLP76 as a binding partner for the cytosolic tail of RAGE and provide a reagent that can block this interaction and protect mice from sepsis in a caecal ligation and puncture model.
- Zhengzheng Yan
- , Haihua Luo
- & Yong Jiang
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Article
| Open AccessCo-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells
Macrophages can be polarized by in vitro culture stimuli into M1 or M2 cells, but microenvironments in vivo are more complex. Here the authors analyze cultured macrophages stimulated with a combination of M1 and M2 stimuli by single-cell RNA sequencing, machine learning, and single-cell secretion profiling to show a surprising level of heterogeneity of response.
- Andrés R. Muñoz-Rojas
- , Ilana Kelsey
- & Kathryn Miller-Jensen
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Article
| Open AccessD-mannose suppresses macrophage IL-1β production
Mannose is present at trace levels in blood and regulates cancer growth. Here the authors show that supraphysiological levels of mannose can also regulate macrophages, limiting their production of IL-1β and increasing resistance of mice to LPS-induced endotoxemia and DSS-induced colitis.
- Simone Torretta
- , Alessandra Scagliola
- & Simone Cardaci
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Article
| Open AccessMacrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques
Inhibition of the metabolic enzyme ATP-citrate lyase can attenuate atherosclerosis by preventing dyslipidemia and potentially also by reducing macrophage-mediated inflammation. Here, the authors show that specific targeting of ACLY in macrophages results in more stable atherosclerotic plaques.
- Jeroen Baardman
- , Sanne G. S. Verberk
- & Jan Van den Bossche
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Article
| Open AccessMyeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation
Inflammation contributes to the development of metabolic disease through incompletely understood mechanisms. Here the authors report that deletion of the transcription factor KLF2 in myeloid cells leads to increased feeding and weight gain in mice with concomitant peripheral and central tissue inflammation, while overexpression protects against diet-induced metabolic disease.
- David R. Sweet
- , Neelakantan T. Vasudevan
- & Mukesh K. Jain
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Article
| Open AccessIL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration
Signaling of IL-33 via its receptor, ST2, has been implicated in macrophage function in tissue repair. Here the authors show, using genetic mouse models and single-cell transcriptomic data, that the IL-33/ST2 axis regulates both ILC2-derived IL-13 and macrophage differentiation/reparative function required for club cell regeneration.
- Rania Dagher
- , Alan M. Copenhaver
- & Marina Pretolani
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Article
| Open AccessOntogeny of arterial macrophages defines their functions in homeostasis and inflammation
Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.
- Tobias Weinberger
- , Dena Esfandyari
- & Christian Schulz
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Article
| Open AccessAndrogen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion
Anti-androgen therapy inhibits prostate cancer (PC) progression, and is thought to act directly on cancer cells. Here the authors show that androgen receptor is expressed on normal and PC-associated macrophages, and its stimulation alters macrophage secretome to promote migration of cultured PC cell lines.
- Bianca Cioni
- , Anniek Zaalberg
- & Andries M. Bergman
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Article
| Open AccessGeneration, localization and functions of macrophages during the development of testis
The developmental origins and functions of testis macrophages remain incompletely characterized. Here, the authors show, using histology, high-dimensional mass cytometry and cell fate-mapping data, that interstitial and peritubular macrophages originate from distinct precursors and contribute distinctly to spermatogenesis.
- Emmi Lokka
- , Laura Lintukorpi
- & Marko Salmi
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Article
| Open AccessSLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling
Macrophages survey their surroundings using macropinocytosis, but its regulation is unclear. Here, the authors report that SLIT2, a known inhibitor of Rac GTPases, is an endogenous inhibitor of macropinocytosis, and that SLIT2 limits the uptake of NOD2 ligands into immune cells and subsequent release of the inflammatory chemokine, CXCL1, in vivo.
- Vikrant K. Bhosle
- , Tapas Mukherjee
- & Lisa A. Robinson
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Article
| Open AccessTriacylglycerol synthesis enhances macrophage inflammatory function
As macrophages switch to a proinflammatory gylcolytic state they start to generate triglyceride-rich lipid droplets, but what function these droplets have in this context is not clear. Here the authors show that this triglyceride synthesis is requisite for prostaglandin E2 production and subsequent inflammatory activation.
- Angela Castoldi
- , Lauar B. Monteiro
- & Edward J. Pearce