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| 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 AccessNeutrophil 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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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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Article
| 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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Article
| 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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Article
| 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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Article
| Open AccessPsychological stress impairs IL22-driven protective gut mucosal immunity against colonising pathobionts
Altered gut microbiome and exacerbation of symptoms at times of psychological stress are feature characteristics of Crohn’s disease. Here authors show in a mouse model that psychological stress impairs IL-22-dependent protective immunity of the ileal mucosa, which allows invasive bacteria to colonise the gut.
- Christopher R. Shaler
- , Alexandra A. Parco
- & Brian K. Coombes
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Article
| 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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Article
| Open AccessThe 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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Article
| Open AccessSpecialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules
T cells are selected in the thymus, through interaction with self-antigens, to remove autoreactive cells. Here the authors show that a specialized thymic dendritic cell subset juxtaposes to microvessels, requires CX3CR1/CX3CL1 for this positioning, and has processes extruding into the blood stream to sample soluble macromolecules and assist in T cell selection.
- Elisabeth H. Vollmann
- , Kristin Rattay
- & Ulrich H. von Andrian
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Article
| Open AccessOptineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling
Optineurin (OPTN) has been implicated in various biological processes, but its function in dendritic cells (DC) maturation is still unclear. Here the authors show, by characterizing Optn-conditional knockout mice, that the loss of OPTN induces Jak2/Stat3 activation and IL-10 production to suppress DC maturation and function, thereby ameliorating autoimmune responses in mice.
- Jiajia Wang
- , Jiaying Wang
- & Qinjie Weng
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Article
| 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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Article
| Open AccessCD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn’s disease
Phenotypic markers that overlap between ILC1 and NK populations have impacted the robust and specific analysis of these immune cell populations. Employing scRNA sequencing here the authors identify CD127+ CD94+ innate lymphoid cells that express granulysin and perforin and are expanded in patients with Crohn’s disease.
- L. Krabbendam
- , B. A. Heesters
- & H. Spits
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Article
| 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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Article
| 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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Article
| Open AccessSequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells
Natural Killer cell development is controlled by two related transcription factors, Eomes and T-bet. Authors show here that while the two factors share a large proportion of their target genes, they regulate distinct developmental processes by differing in their pattern of expression and in their associated co-factors.
- Jiang Zhang
- , Stéphanie Le Gras
- & Thierry Walzer
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Article
| Open AccessMetabolic requirements of NK cells during the acute response against retroviral infection
Metabolic alterations control the fate and function of immune cells in response to infections, but the function of NK cell metabolism in the context of acute viral infections is unclear. Here the authors show that acute NK cell responses to Friend retrovirus involve increased glycolysis and mitochondrial metabolism and require amino acid transport as well as iron sufficiency.
- Elisabeth Littwitz-Salomon
- , Diana Moreira
- & David K. Finlay
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Article
| 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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Article
| Open AccessCD11b+ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation
Dendritic cells in the lung may be specialised to mediate specific types of immune function. Here the authors show that subpopulations of mouse CD11b+ lung DC at different stages of maturation and phenotype can promote Th17 or Th2 CD4+ T cell differentiation.
- Gentaro Izumi
- , Hideki Nakano
- & Donald N. Cook
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Article
| 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 AccessPD-L1+ and XCR1+ dendritic cells are region-specific regulators of gut homeostasis
Dendritic cells initiate and regulate adaptive immunity and differ according to gut anatomical location. Here the authors show that DC residing in the upper and lower intestines show differential PD-L1 and XCR1 expression and drive specific T cell responses to prevent gut inflammation.
- Thais G. Moreira
- , Davide Mangani
- & Howard L. Weiner
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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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Article
| Open AccessFcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity
Neutrophils are versatile immune cells that may also serve as antigen-presenting cells (APC). Here the authors show that engaging FcγRs on neutrophils with immune complexes or an anti-FcγR-antigen conjugate induces neutrophil APC with comparable functions as classical dendritic cells, and with therapeutic potentials for cancer and infectious diseases.
- Vijayashree Mysore
- , Xavier Cullere
- & Tanya N. Mayadas
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Article
| Open AccessMAIT cells regulate NK cell-mediated tumor immunity
Mucosal-associated invariant T (MAIT) cells facilitate anti-microbial responses, but their functions in cancer protection is unclear. Here the authors show that activated MAIT cells induce an IFN-γ transcriptome in natural killer (NK) cells and enhance NK-dependent anti-cancer immunity in mice, thereby hinting a new avenue for cancer therapy.
- Emma V. Petley
- , Hui-Fern Koay
- & Phillip K. Darcy
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Article
| Open AccessEnhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis
Biomarkers to indicate potential response to biologic therapeutics are needed for patients with psoriasis. Here the authors show that phosphorylation of NFκBp65 in cDC2 before therapy is an indication of non-response to the anti-TNF therapy adalimumab in patients with psoriasis.
- Rosa Andres-Ejarque
- , Hira Bahadur Ale
- & Deborah Stocken
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Article
| Open AccessNK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence
During wound healing and infection in the skin there is a hypoxic environment involving HIF-1α and NK cells. Here the authors show that NK cells through HIF-1α provide a cross-regulatory balance to provide an adequate antimicrobial defence that can inhibit subsequent wound healing.
- Michal Sobecki
- , Ewelina Krzywinska
- & Christian Stockmann
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Article
| Open AccessEndogenous 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| Open AccessSerum amyloid P component is an essential element of resistance against Aspergillus fumigatus
Serum Amyloid P is a humoral component with established roles in the response to bacterial infection and regulation of tissue remodeling. Here the authors provide evidence to a further crucial role of serum amyloid P in the context of fungal pathogen Aspergillus fumigatus.
- Andrea Doni
- , Raffaella Parente
- & Alberto Mantovani
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Article
| Open AccessTcpC 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 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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Article
| Open AccessA 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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Article
| 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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Article
| 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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Article
| Open AccessThe 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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Article
| Open AccessRole 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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Article
| Open AccessPPARɣ drives IL-33-dependent ILC2 pro-tumoral functions
Group 2 innate lymphoid cells (ILC2s) are a component of type 2 immune response recently described to be involved in the regulation of anti-tumor immune responses. Here, the authors show that the expression of the peroxisome proliferator-activated receptor γ (PPAPγ) in human and mouse ILC2 sustains type-2 cytokines secretion and support their pro-tumorigenic role in preclinical cancer models.
- Giuseppe Ercolano
- , Alejandra Gomez-Cadena
- & Camilla Jandus
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Article
| Open AccessCD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma
The role of the CD200–CD200R axis in regulating pulmonary inflammation is not completely understood. Here the authors show CD200R is expressed on type 2 innate lymphoid cells (ILC2s), and its engagement by CD200 ameliorates airway hyperreactivity and allergic asthma via inhibition of NF-κB signaling.
- Pedram Shafiei-Jahani
- , Doumet Georges Helou
- & Omid Akbari
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Article
| 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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Article
| 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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Article
| 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 AccessHuman anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells
Epithelial tissue mononuclear phagocytes (MNP) can transmit HIV to CD4 T cells, but less is known about sub-epithelial cells. Here, the authors describe MNPs in human anogenital and colorectal tissues and find that CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 preferentially take up and transmit HIV.
- Jake W. Rhodes
- , Rachel A. Botting
- & Andrew N. Harman