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| Open AccessHistone deacetylase 3 controls lung alveolar macrophage development and homeostasis
Alveolar macrophages are known to derive from embryonic precursors although the regulation of this process is poorly understood. Here the authors propose a key role for histone deacetylase 3 as an epigenetic regulator of lung alveolar macrophage development.
- Yi Yao
- , Queping Liu
- & Qing-Sheng Mi
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Article
| Open AccessMucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity
Inflammation, immune cells and the host microbiota are intimately linked in the pathophysiology of obesity and diabetes. Here the authors show mucosal-associated invariant T cells fuel inflammation in the tissues and serve a function in promoting metabolic breakdown, polarising macrophage populations and inducing dysbiosis of the intestinal microbiota.
- Amine Toubal
- , Badr Kiaf
- & Agnès Lehuen
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Article
| Open AccessMG53 suppresses interferon-β and inflammation via regulation of ryanodine receptor-mediated intracellular calcium signaling
TRIM proteins are known to play critical roles in the context of viral infection. Here the authors establish MG53 (TRIM72) suppresses IFN and inflammation by modulation of ryanodine receptor related intracellular calcium induction.
- Matthew Sermersheim
- , Adam D. Kenney
- & Jianjie Ma
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Article
| Open AccessRETRACTED ARTICLE: Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection
Kupffer cells are more resistant to M. tuberculosis when compared with alveolar macrophages. Here the authors show that this distinction is caused by the presence of ornithine and imidazole in Kupffer cells and that these metabolites can drive autophagy and M. tuberculosis killing in alveolar macrophages when given intranasally to infected mice.
- Ramya Sivangala Thandi
- , Rajesh Kumar Radhakrishnan
- & Ramakrishna Vankayalapati
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| Open AccessImmune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles
Extracellular vesicles can carry immunoregulatory cytokines such as TGF-β. Here the authors use CD11b-deficient mice and macrophages to show that such vesicles carrying TGF-β are produced in response to Candida albicans infections and can limit the proinflammatory response partly via a positive feedback on TGF-β production by endothelial cells.
- Luke D. Halder
- , Emeraldo A. H. Jo
- & Christine Skerka
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Article
| Open AccessNegative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression
Macrophage activation is integral to innate immunity and inflammation, and involves transcriptome remodeling leading to the rapid upregulation of pro- and anti-inflammatory effector genes. Here the authors show that the negative elongation factor (NELF) complex controls the transcription of anti-inflammatory genes through Pol II pause release.
- Li Yu
- , Bin Zhang
- & Xiaoyu Hu
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Article
| Open AccessDistinct fate, dynamics and niches of renal macrophages of bone marrow or embryonic origins
Renal macrophages (RMs) can be of bone marrow or embryonic origin, but their abundance, fate and metabolic profiles in physiological and pathogenic settings are still unclear. Here the authors show, by characterizing these two RMs in multiple transgenic mouse lines, that they exhibit distinct dynamics, homeostasis, immune activity, and metabolic properties.
- Fengming Liu
- , Shen Dai
- & Xuebin Qin
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Article
| Open AccessThe platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure
The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.
- Abhishek Chauhan
- , Lozan Sheriff
- & Patricia F. Lalor
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Article
| Open AccessGlycogen metabolism regulates macrophage-mediated acute inflammatory responses
Glycogen can be metabolized via glycogenolysis and the pentose phosphate pathway as well as into the production of UDP glucose, which when secreted can bind the P2Y14 receptor. Here the authors show how these glycogen metabolism pathways contribute to proinflammatory macrophage activation and susceptibility to sepsis.
- Jingwei Ma
- , Keke Wei
- & Bo Huang
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Article
| Open AccessRXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression
Macrophages can differentiate to perform homeostatic tissue-specific functions. Here the authors show that RXR signalling is critical for large peritoneal macrophage (LPM) expansion during neonatal life and LPM lipid metabolism and survival during adult homeostasis, and that ovarian cancer growth relies on RXR-dependent LPMs.
- María Casanova-Acebes
- , María Piedad Menéndez-Gutiérrez
- & Mercedes Ricote
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Article
| Open AccessPerivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome
Lamina propria macrophages are at the frontline of defense against intestinal pathogens. Here the authors reveal that CCR2 and NR4A1-dependent CX3CR1+ macrophages form a dense network around the vessels in the lamina propria, and implicate this anatomical structure into prevention of systemic bacterial dissemination.
- Masaki Honda
- , Bas G. J. Surewaard
- & Paul Kubes
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Article
| Open AccessMacrophages employ quorum licensing to regulate collective activation
Macrophage activation is tightly regulated to maintain immune homeostasis, yet activation is also heterogeneous. Here, the authors show that macrophages coordinate activation by partitioning into two phenotypes that can nonlinearly amplify collective inflammatory cytokine production as a function of cell density.
- Joseph J. Muldoon
- , Yishan Chuang
- & Joshua N. Leonard
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Article
| Open AccessNitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
Production of inflammatory mediators by M1-polarized macrophages is thought to rely on suppression of mitochondrial metabolism in favor of glycolysis. Refining this concept, here the authors define metabolic targets of nitric oxide as responsible for the mitochondrial rewiring resulting from polarization.
- Erika M. Palmieri
- , Marieli Gonzalez-Cotto
- & Daniel W. McVicar
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Article
| Open AccessAfrican-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin
A polymorphism in human TP53 (P47S) that predominantly exists in individuals of African descent affects ferroptosis. Here, the authors show that this results in iron accumulation in macrophages leading to more productive infection by intracellular bacteria but improved anti-inflammatory response to the malarial toxin hemozoin.
- Kumar Sachin Singh
- , Julia I-Ju Leu
- & Farokh Dotiwala
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Article
| Open AccessMicroparticle traction force microscopy reveals subcellular force exertion patterns in immune cell–target interactions
Traction force microscopy is an effective method for measuring cellular forces but it is limited by planar geometry. Here the authors develop a facile method to produce deformable hydrogel particles and a reference-free computational method to resolve surface traction forces from particle shape deformation.
- Daan Vorselen
- , Yifan Wang
- & Julie A. Theriot
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Article
| Open AccessTrained immunity modulates inflammation-induced fibrosis
Innate immune cells can be trained by some stimuli or pathogen exposures to be metabolically and epigenetically altered such that they have different responses to subsequent exposures. Here the authors show that low-dose LPS trained macrophages and BCG-trained macrophages have opposing effects on fibrosis and inflammation in the context of systemic sclerosis.
- Mohamed Jeljeli
- , Luiza Gama Coelho Riccio
- & Frédéric Batteux
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Article
| Open AccessBrain-to-cervical lymph node signaling after stroke
Brain damage induces systemic inflammation, but insights and implication of this induction is still unclear. Here the authors show, using rat and mouse focal cerebral ischemia models, that the damaged brain signals via the VEGF-C/VEFGR3 axis to activate inflammatory responses in the draining cervical lymph nodes to induce systemic inflammation.
- Elga Esposito
- , Bum Ju Ahn
- & Kazuhide Hayakawa
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Article
| Open AccessLeishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition
NLRP3 activation by Leishmania parasites is critical to the outcome of the disease. Here the authors show that LRV, a virus infecting Leishmania strains associated with more severe human disease, enables the parasite to suppress the inflammasome by activating type 1 interferon through TLR3, which leads to autophagy-mediated NLRP3 degradation.
- Renan V. H. de Carvalho
- , Djalma S. Lima-Junior
- & Dario S. Zamboni
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| Open Access4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects
Redirection of the TCA cycle intermediate aconitate to itaconate production has anti-inflammatory effects. Here the authors show that the itaconate derivative 4-octyl-itaconate is anti-inflammatory partly as a result of inhibiting GAPDH enzymatic activity and thereby glycolysis in macrophages.
- Shan-Ting Liao
- , Chao Han
- & Ling-Yi Kong
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Article
| Open AccessContext-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele
Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of monocytes in IL-7-related autoimmunity.
- Hussein Al-Mossawi
- , Nicole Yager
- & Benjamin P. Fairfax
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Article
| Open AccessModulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24
Stat6 promotes M2 macrophage polarization. Here the authors characterize Trim24-CBP-Stat6 circuit regulating M2 macrophage polarization via Stat6 acetylation, and show it contributes to pro-tumorigenic macrophage activity in mice.
- Tao Yu
- , Shucheng Gan
- & Yichuan Xiao
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Article
| Open AccessImmGen report: sexual dimorphism in the immune system transcriptome
Sexual dimorphism is observed frequently in immune disorders, but the underlying insights are still unclear. Here the authors analyze transcriptome and epigenome changes induced by interferon in various mouse immune cell types, and find only a restricted set of sexual dimorphism genes in innate immunity and macrophages.
- Shani Talia Gal-Oz
- , Barbara Maier
- & Tal Shay
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Article
| Open AccessNa+-H+ exchanger 1 determines atherosclerotic lesion acidification and promotes atherogenesis
Na+-H+ exchanger 1 (Nhe1) regulates extracellular pH by extruding protons in exchange for extracellular Na+ . Here, Liu et al. show that Nhe1 promotes the development and acidification of atherosclerotic lesions and that pH-sensitive probes can be used to monitor plaque growth and acidification.
- Cong-Lin Liu
- , Xian Zhang
- & Guo-Ping Shi
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| Open AccessNon-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung
Functional diversity of tissue-resident macrophages and signals governing their ontogeny and turnover remain unknown for the majority of tissues. Here the authors describe two phenotypically and functionally distinct long-lived populations of lung interstitial macrophages and their putative blood-derived monocytic precursor.
- Joey Schyns
- , Qiang Bai
- & Thomas Marichal
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Article
| Open AccessMacrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry
Tumor associated macrophages are functionally and phenotypically heterogeneous. Here the authors describe the spatial distribution of distinct macrophage populations within regions of gastric cancer and probe their associations with clinical outcomes, gene signatures and PDL1 expression.
- Yu-Kuan Huang
- , Minyu Wang
- & Alex Boussioutas
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Article
| Open AccessIFN-β is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation
Clearance of apoptotic neutrophils by macrophages is important for the resolution of inflammation. Here, the authors show that interferon-β produced by resolution phase macrophages promotes neutrophil apoptosis and efferocytosis and induces macrophage reprogramming to a pro-resolving phenotype, thereby identifying IFN-β as a multi-pronged pro-resolution cytokine.
- Senthil Kumaran Satyanarayanan
- , Driss El Kebir
- & Amiram Ariel
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Article
| Open AccessIFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation
Macrophage activation is synergistically controlled by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Here the authors show that IFN-γ promotes macrophage activation not only by activating STAT1-dependent genes, but also by suppressing STAT3-dependent negative feedback regulation downstream of LPS signaling.
- Kyuho Kang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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Article
| Open AccessDeletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
The lineage-specific receptor CSF1R controls macrophage development and homeostasis. Here the authors show that deletion of a conserved Csf1r enhancer (FIRE) selectively depletes brain microglia and resident macrophages in the epidermis, kidney, heart and peritoneum of otherwise healthy mice.
- Rocío Rojo
- , Anna Raper
- & Clare Pridans
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Article
| Open AccessInflammation triggers immediate rather than progressive changes in monocyte differentiation in the small intestine
Bone marrow-derived monocytes are recruited to the gut to replenish the local macrophage pool. Here the authors show that, while such replenishment constitutively occur under homeostasis, gut inflammation induces an immediate, Trem1-related transcription change to recruited monocyte to enable a context-dependent modulation of macrophage functions.
- Girmay Desalegn
- & Oliver Pabst
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Article
| Open AccessTherapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
Dimethyl fumarate (DMF) is an established treatment for relapsing multiple sclerosis with unclear mechanism of action. Here the authors distinguish DMF responders by monocyte counts and redox gene signature in a prospective longitudinal cohort at 3 month of therapy, and associate NOX3 genetic variants with outcome.
- Karl E. Carlström
- , Ewoud Ewing
- & Fredrik Piehl
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Article
| Open AccessSerum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies
FHR1 is a serum protein implicated in complement regulation. Here the authors show that human FHR1 binds to necrotic cells, triggering inflammasome activation in monocytes in culture, localizes to necrotic tissue and correlates with inflammatory cytokine levels in vasculopathies.
- Sarah Irmscher
- , Silke R. Brix
- & Christine Skerka
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Article
| Open AccessLipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace
The diversity of human mononuclear phagocyte subsets remains to be characterized in many tissue-specific and functional contexts, including pulmonary inflammation. Here the authors characterize dendritic cell and monocyte subset recruitment to the bronchoalveolar space in a human LPS inhalation model.
- Laura Jardine
- , Sarah Wiscombe
- & A. John Simpson
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Article
| Open AccessMajor vault protein suppresses obesity and atherosclerosis through inhibiting IKK–NF-κB signaling mediated inflammation
Metabolic diseases are associated with chronic, low-grade inflammation. Here the authors show that major vault protein (MVP) suppresses NF-κB signalling in macrophages via an IRAK1–TRAF6 axis and that loss of MVP in myeloid cells exacerbates the inflammatory response in mice fed a high fat diet.
- Jingjing Ben
- , Bin Jiang
- & Qi Chen
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Article
| Open AccessCoordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single macrophages infected with Candida albicans
The outcomes of the interactions between individual host cells and pathogens are heterogeneous. Here, the authors assess transcriptional variability in both host and pathogen during infection of macrophages with the fungus Candida albicans, using sorted subpopulations and single macrophages.
- José F. Muñoz
- , Toni Delorey
- & Christina A. Cuomo
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Article
| Open AccessNeutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair
Neutrophils and macrophages are both involved in the initiation of inflammation, but whether and how they may participate in inflammation resolution is unclear. Here the authors show that neutrophils may mediate the conversion of macrophage into a pro-resolution phenotype via reactive oxygen species production to promote liver repair.
- Wenting Yang
- , Yuandong Tao
- & Li Tang
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Article
| Open AccessGenetic programming of macrophages generates an in vitro model for the human erythroid island niche
In vitro differentiation of red blood cells (RBCs) is a desirable therapy for various disorders. Here the authors develop a culture system using stem cell-derived macrophages to show that inducible expression of a transcription factor, KLF1, enhances RBC production, potentially through the induction of three soluble factors, ANGPTL7, IL33 and SERPINB2.
- Martha Lopez-Yrigoyen
- , Cheng-Tao Yang
- & Lesley M. Forrester
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Article
| Open AccessSympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A
Diverse interactions between the nervous and immune systems have been shown, but specific mechanistic insights are still lacking. Here the authors show, using both mouse inflammation models and clinical correlation, that adrenergic nerve may ameliorate inflammation by inducing repulsive guidance molecule A signalling.
- Andreas Körner
- , Martin Schlegel
- & Valbona Mirakaj
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Article
| Open AccessCKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ
In atherosclerotic plaques, transformation of macrophages into foam cells is a key step in initiating the inflammatory response. Here Fan et al. show that casein kinase 2-interacting protein-1 (CKIP-1) limits foam cell formation and atherosclerosis by preventing expression of the scavenger receptor LOX-1 through REGγ-mediated degradation of Oct-1.
- Jiao Fan
- , Lifeng Liu
- & Lingqiang Zhang
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Article
| Open AccessDiverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages
Transcription factors of the AP-1 family can play diverse roles despite recognizing the same DNA sequence. Here the authors investigate the DNA binding activities of AP-1 members in mouse macrophages and apply a machine learning approach to identify motifs predicted to drive factor-specific binding profiles.
- Gregory J. Fonseca
- , Jenhan Tao
- & Christopher K. Glass
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Article
| Open AccessFetal-derived macrophages dominate in adult mammary glands
Tissue-resident macrophages are highly specialized phagocytes that serve multiple functions. Here, using high-dimension analyses and fate-mapping experiments, the authors show that fetal liver-derived macrophages dominate the mammary gland in neonatal and adult, and display characteristic phenotypes and functions.
- Norma Jäppinen
- , Inês Félix
- & Marko Salmi
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Article
| Open AccessA miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset
A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.
- Dorothée Selimoglu-Buet
- , Julie Rivière
- & Eric Solary
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Article
| Open AccessIntegrin CD11b activation drives anti-tumor innate immunity
Recruitment of myeloid cells can be regulated by integrin CD11b. Here the authors show that in the tumor microenvironment, CD11b is not essential for recruitment of myeloid cells but rather induces macrophage anti-tumorigenic polarization via stimulating let7a and NFκB signaling and that pharmacological activation of CD11b enhances survival in mouse models of cancer.
- Michael C. Schmid
- , Samia Q. Khan
- & Judith A. Varner
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Article
| Open AccessCSF1R regulates the dendritic cell pool size in adult mice via embryo-derived tissue-resident macrophages
Dendritic cells (DC) are important regulators of both innate and adaptive immunity, but how the DC pool is homeostatically maintained in vivo is unclear. Here the authors show that combined deficiency of FLT3 and CSF1R impedes the differentiation of spleen macrophages of embryonic origin that are required for DC homeostasis.
- Gulce Itir Percin
- , Jiri Eitler
- & Claudia Waskow
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Article
| Open AccessBioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections
Pulmonary infections constitute a substantial health problem worldwide. Here the authors show that phagocytes similar to primitive macrophages can be generated from human induced pluripotent stem cells, by the use of industry-compatible, stirred-tank bioreactors, and applied as a cell-based therapy to treat acute bacterial infections in mice.
- Mania Ackermann
- , Henning Kempf
- & Nico Lachmann
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Article
| Open AccessMacrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells
Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix degradation. Here Hadi et al. identify a netrin-1/neogenin-based crosstalk between macrophages and vascular smooth muscle cells (VSMCs), leading to the secretion of the matrix metalloproteinase MMP-3 by VSMCs and subsequent matrix degradation in AAA lesions.
- Tarik Hadi
- , Ludovic Boytard
- & Bhama Ramkhelawon
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Article
| Open AccessCompetitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
Brain microglial cells can be replenished by blood-derived monocytes, but many aspects of this repopulation remain unclear. Here the authors show that the brain microglial niche can be replaced both by proliferating, residential microglia as well as differentiated Ly6Chi monocytes, with the latter having overlapping but distinct characteristics.
- Harald Lund
- , Melanie Pieber
- & Robert A. Harris
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Article
| Open AccessThe deubiquitinase MYSM1 dampens NOD2-mediated inflammation and tissue damage by inactivating the RIP2 complex
The innate immune receptor NOD2 is tightly regulated to ensure beneficial antimicrobial immunity. Here the authors show that the H2A deubiquitinase MYSM1 restrains NOD2 signaling by removing lysine 63 (K63), K27, M1 but not K48 polyubiquitin chains from its downstream adaptor protein RIP2.
- Swarupa Panda
- & Nelson O. Gekara
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Article
| Open AccessPOH1 deubiquitinates pro-interleukin-1β and restricts inflammasome activity
The inflammasomes are important for activating the pro-inflammatory cytokine interleukin-β (IL-1β) for protection against pathogens. Here the authors show that a deubiquitinase, POH1, reduces the conversion of pro-IL-1β into its active form, with in vivo data further implicating a role of POH1 for maintaining immune homeostasis.
- Li Zhang
- , Yun Liu
- & Yongzhong Liu
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Article
| Open AccessStatin as a novel pharmacotherapy of pulmonary alveolar proteinosis
Pulmonary alveolar proteinosis (PAP) is associated with defective macrophage clearance of surfactant. Here, the authors show that patients with PAP have altered cholesterol-to-phospholipid ratio in their surfactant, and that more importantly, statin therapy and reduction of cholesterol accumulation in macrophages can ameliorate PAP in both humans and mice.
- Cormac McCarthy
- , Elinor Lee
- & Bruce C. Trapnell