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| Open AccessHuman in vivo-generated monocyte-derived dendritic cells and macrophages cross-present antigens through a vacuolar pathway
Cross-presentation, or the presentation of exogenous antigens on MHC-I, is thought to be restricted to dendritic cells (DCs). Here the authors show that human DCs and macrophages developed in vivo from monocytes can both perform cross-presentation using a non-conventional pathway, but only DCs are capable of inducing cytotoxic CD8+ T cells.
- Tsing-Lee Tang-Huau
- , Paul Gueguen
- & Elodie Segura
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Article
| Open AccessFactor XIIIA—expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking
Lung squamous carcinomas (LUSC) are poorly molecularly characterized, but sub-populations show promising response to immune checkpoint inhibitors. Here, the authors identify a subset of LUSC characterized by infiltration of inflammatory monocytes, where metastasis is linked to Factor XIIIA promoting fibrin cross-linking.
- Alessandro Porrello
- , Patrick L. Leslie
- & Chad V. Pecot
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| Open AccessWASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis
Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.
- Amlan Biswas
- , Dror S. Shouval
- & Scott B. Snapper
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| Open AccessThe E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome
The NLRP3 inflammasome is important for inducing IL-1β and IL-18 inflammatory responses. Here the authors show, by generating and characterizing Peli2 deficient mice and immune cells, that an E3 ubiquitin ligase Pellino2 promotes inflammasome priming by inducing NLRP3 ubiquitination and by targeting IRAK1.
- Fiachra Humphries
- , Ronan Bergin
- & Paul N. Moynagh
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Article
| Open AccessCanonical PI3Kγ signaling in myeloid cells restricts Trypanosoma cruzi infection and dampens chagasic myocarditis
Trypanosoma cruzi infection causes Chagas disease, but mechanisms underlying pathogenesis are unclear. Here, Silva et al. show that canonical PI3Kγ signaling in myeloid cells restricts T. cruzi infection in mice and that high PIK3CG expression correlates with low parasite levels in human Chagas’ hearts.
- Maria C. Silva
- , Marcela Davoli-Ferreira
- & Thiago M. Cunha
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Article
| Open AccessMacrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis
The authors previously developed a mouse model of parenteral nutrition-associated cholestasis (PNAC) that is dependent on parenteral phytosterols and intestinal injury with DSS. Here they refine the model and show that PNAC pathology is dependent on recruitment of hepatic macrophages and IL-1 signaling.
- Karim C. El Kasmi
- , Padade M. Vue
- & Ronald J. Sokol
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| Open AccessDirect conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue
At the site of injury, macrophages exit their characteristic phenotype undergoing direct conversion to fibroblasts. Keratinocyte-derived miR-21, packaged in extracellular vesicles, enables such plasticity which accounts for the vast majority of all fibroblasts in the granulation tissue.
- Mithun Sinha
- , Chandan K. Sen
- & Sashwati Roy
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Article
| Open AccessMT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis
Matrix metalloproteinases (MMP) are involved in vascular remodeling associated with plaque progression. Little is known about their immune regulatory role in vascular disorders. Here, the authors report that MT4-MMP-deficiency increases the recruitment of patrolling monocytes to early atherosclerotic lesions, which accelerates atherosclerosis.
- Cristina Clemente
- , Cristina Rius
- & Alicia G. Arroyo
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Article
| Open AccessChloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype
Tumour-associated macrophages (TAMs) display an M2 phenotype that promote tumour immune escape. Here the authors show that Chloroquine (CQ), a lysosome inhibitor used against malaria, inhibits tumour growth by switching TAMs into an M1 tumor-killing phenotype by repolarizing macrophages metabolism.
- Degao Chen
- , Jing Xie
- & Bo Huang
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| Open AccessThe tumour microenvironment creates a niche for the self-renewal of tumour-promoting macrophages in colon adenoma
Tissue-resident F4/80hi macrophages can be found both in normal gut as well as in intestinal tumours. Here the authors show that in the colon these macrophages are CCR2-dependent, while in tumours they gain the ability to self-renew, relying on CSF1 and promoting cancer progression.
- Irene Soncin
- , Jianpeng Sheng
- & Christiane Ruedl
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Article
| Open AccessHuman macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity
M1 and M2 cells are representative of proinflammatory versus resolving macrophages, respectively. Here the authors characterize the lipid mediator response to bacterial infection by these cells and show that differing panels of leukotrienes and specialized pro-resolving mediators contribute to control of the dichotomy.
- Oliver Werz
- , Jana Gerstmeier
- & Charles N. Serhan
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| Open AccessDiabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages
Type 2 diabetes is associated with impaired wound healing, which can lead to limb loss. Here, the authors show that in Type 2 diabetic mouse models, Dnmt1 is upregulated in hematopoietic stem cells, leading to impaired differentiation towards macrophages, reduced macrophage infiltration in the wound and skewed M1/M2 polarization.
- Jinglian Yan
- , Guodong Tie
- & Louis M. Messina
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Article
| Open AccessThe podoplanin-CLEC-2 axis inhibits inflammation in sepsis
Sepsis is a life-threatening condition where exaggerated inflammatory responses lead to severe tissue damage. Here, Rayes and colleagues show that the interaction between podoplanin and its receptor CLEC-2 on platelets plays a critical role in limiting inflammation during sepsis.
- Julie Rayes
- , Siân Lax
- & Steve P. Watson
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| Open AccessPro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4–MD2 complex
Reactive species of oxygen promote the development of hepatic steatosis. Here, Kim et al. demonstrate that palmitate stimulates macrophage infiltration and increases oxidative stress during steatosis by binding to the TLR4–MD2 complex, which results in the activation of NOX2.
- So Yeon Kim
- , Jong-Min Jeong
- & Won-Il Jeong
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Article
| Open AccessPeritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels
Tissue-resident marcophages have both generic and tissue-specific functions, but how the latter functions are imbued is still unclear. Here the authors show that peritoneal macrophages express a specialised genetic programme to utilise the locally enriched glutamate for a metabolic setting that facilitates protective in situ immunity.
- Luke C. Davies
- , Christopher M. Rice
- & Daniel W. McVicar
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Article
| Open AccessLoss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease
Circadian controls of immune responses by the molecular clock have been reported, but the underlying mechanisms are unclear. Here the authors show that the master circadian gene, Bmal1, is essential for modulating the homeostasis of myeloid cells to control pro-inflammatory IL-17+/IFN-γ+ T cells in autoimmunity.
- Caroline E. Sutton
- , Conor M. Finlay
- & Annie M. Curtis
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| Open AccessGlucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages
Glucocorticoid reduces inflammation by both inducing anti-inflammatory genes and suppressing pro-inflammatory genes, but how these two functions are dictated is unclear. Here the authors show that phosphorylated glucocorticoid receptor-interacting protein 1 (GRIP1) serves as a coactivator for this response in macrophage.
- David A. Rollins
- , Joubert B. Kharlyngdoh
- & Inez Rogatsky
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| Open AccessMafB is a critical regulator of complement component C1q
Complement component C1q activates efferocytosis, suppresses inflammatory responses, and is thereby thought to limit autoimmune disease. Here, the authors show that macrophage transcription factor MafB regulates total serum levels of C1q, which contributes to preventing autoimmune disease in mice.
- Mai Thi Nhu Tran
- , Michito Hamada
- & Satoru Takahashi
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| Open AccessVSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism
Macrophage differentiation and inflammatory function are controlled by cell metabolism. Here, the authors use a viral hepatitis model and a high-fat diet model of insulin resistance to show how VSIG4 inhibits inflammatory macrophage activation by modulating mitochondrial pyruvate metabolism.
- Jialin Li
- , Bo Diao
- & Yuzhang Wu
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Article
| Open AccessNMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury
Damage-associated molecular patterns (DAMP) are important mediators of innate immunity. Here the authors show that N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs to promote inflammation by activating macrophages via the Toll-like receptor 4 and NF-κB pathways.
- Zhikai Xiahou
- , Xiangli Wang
- & Huanhuan Liang
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| Open AccessBlood vessel control of macrophage maturation promotes arteriogenesis in ischemia
Molecular mechanisms of macrophage-mediated regulation of artery growth in response to ischemia are poorly understood. Here the authors show that vascular endothelium controls macrophage maturation and differentiation via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery.
- Kashyap Krishnasamy
- , Anne Limbourg
- & Florian P. Limbourg
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| Open AccessAn NF-κB-microRNA regulatory network tunes macrophage inflammatory responses
MicroRNAs (miR) are important regulators of gene transcription, with miR-155 and miR-146a both implicated in macrophage activation. Here the authors show that NF-κB signalling, miR-155 and miR-146a form a complex network of cross-regulations to control gene transcription in macrophages for modulating inflammatory responses.
- Mati Mann
- , Arnav Mehta
- & David Baltimore
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Article
| Open AccessAlveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice
Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.
- Wenqian He
- , Chi-Jene Chen
- & Gene S. Tan
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Article
| Open AccessCaspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs
Tumor associated macrophages (TAMs) promote cancer progression. Here, the author show that caspase-1 promotes TAMs differentiation by attenuating medium-chain acyl-CoA dehydrogenase activity and that inhibition of this axis results in suppression of tumour growth in a transgenic mouse model of breast cancer.
- Zhiyuan Niu
- , Qian Shi
- & Pingping Shen
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Article
| Open AccessCLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation
The NLRP3 inflammasome is key to the regulation of innate immunity against pathogens or stress, but the underlying signaling regulation is still unclear. Here the authors show that chloride intracellular channels (CLIC) interface between mitochondria stress and inflammasome activation to modulate inflammatory responses.
- Tiantian Tang
- , Xueting Lang
- & Rongbin Zhou
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Article
| Open AccessBCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases
BCATs catabolize leucine and other BCAAs. Here the authors show that BCAA metabolism affects the broken Krebs cycle, reprogramming macrophages to be less proinflammatory, and show that BCAT1 inhibitor ERG240 can treat arthritis in mice and glomerulonephritis in rats.
- Adonia E. Papathanassiu
- , Jeong-Hun Ko
- & Jacques Behmoaras
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| Open AccessHuman LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes
LACC1 genetic variants are associated with Crohn's disease, leprosy and arthritis. Here the authors show that LACC1 is needed for optimal innate receptor-induced signalling, mitochondrial ROS production and microbial clearance, effects that are reduced by a Crohn's disease-risk variant in LACC1.
- Amit Lahiri
- , Matija Hedl
- & Clara Abraham
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| Open AccessLeukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα
The binding of the leukocyte integrin Mac1 to the platelet receptor GPIbα is important for the physiological response to tissue injury. Here the authors show that this interaction also regulates thrombosis, without influencing bleeding time, which may provide clues for the development of new anti-thrombotic drugs.
- Yunmei Wang
- , Huiyun Gao
- & Daniel I. Simon
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Article
| Open AccessTNFα drives mitochondrial stress in POMC neurons in obesity
Long-term consumption of a calorie-rich diet persistently activates brain microglia. Here, the authors show that microglial activity in mouse brains oscillates daily in conjunction with feeding, and that TNFα, secreted by activated microglia, induces mitochondrial stress in satiety-promoting POMC neurons.
- Chun-Xia Yi
- , Marc Walter
- & Matthias H. Tschöp
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| Open AccessExploiting induced pluripotent stem cell-derived macrophages to unravel host factors influencing Chlamydia trachomatis pathogenesis
In vitro models to study the role of host genetics in the response to chlamydial infection are limited. Here, Yeung et al. show that macrophages derived from human induced pluripotent stem cells (which can be genetically manipulated) support chlamydial infection and can be used for this purpose.
- Amy T. Y. Yeung
- , Christine Hale
- & Robert E. W. Hancock
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| Open AccessRegulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection
Cytokines and their associated pathways can affect survival ofMycobacterium tuberculosis in macrophages, representing potential targets for host-directed therapies. Here, Péan et al. show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplet homeostasis.
- Claire B. Péan
- , Mark Schiebler
- & Marc S. Dionne
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| Open AccessIFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP
The role of IFI16 as a DNA sensor is highly controversial. With support from a Nature Communications back-to-back publication from Almineet al. the authors here provide functional evidence that IFI16 is required for DNA sensing via the cGAS-STING pathway in human macrophages.
- K. L. Jønsson
- , A. Laustsen
- & M. R. Jakobsen
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| Open AccessmTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis
mTORC1 and mTORC2 are alternatively required for differentiation of T cells into Th1/Th17 or Th2 cells. Here the authors show mTORC2 signalling is also needed for IL-4-induced M2 activation with functional evidence provided by aN. brasiliensisinfection model and cold challenge to model adaptive thermogenesis.
- R. W. Hallowell
- , S. L. Collins
- & M. R. Horton
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Article
| Open AccessSCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages
Toll-like receptors engage TIR domain-containing adaptors to control proinflammatory gene expression in response to pathogens and tissue damage. Here the authors show that the non-TIR domain-containing transmembrane protein SCIMP is a previously unrecognized TLR adaptor expressed by macrophages.
- Lin Luo
- , Nilesh J. Bokil
- & Matthew J. Sweet
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| Open AccessPolyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease
In vivo imaging of inflammation is crucial for detection and monitoring of many pathologies and noninvasive macrophage quantification has been suggested as a possible approach. Here Keliher et al. describe novel polyglucose nanoparticle tracers that are rapidly excreted by the kidney and with high affinity for macrophages in atherosclerotic plaques.
- Edmund J. Keliher
- , Yu-Xiang Ye
- & Matthias Nahrendorf
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| Open AccessMacrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice
Ventricular arrhythmia is a leading cause of death in patients with diabetes. Here the authors show that inflammasome activation and ILK-1β production in cardiac macrophages cause arrhythmia in diabetic mice, which can be successfully treated using agonists to IL-1β receptor or NLRP3 inhibitors.
- Gustavo Monnerat
- , Micaela L. Alarcón
- & Emiliano Medei
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Article
| Open AccessPARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation
Signalling pathways that mediate macrophage activation in disease are poorly understood. Here the authors show that inhibition of PARP9 and/or activation of PARP14 may attenuate macrophage-mediated vascular diseases, and also provide new insight into the development of effective therapies for other inflammatory disorders.
- Hiroshi Iwata
- , Claudia Goettsch
- & Masanori Aikawa
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Article
| Open AccessPolarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals
The role of nutrient-sensing pathways in regulation of innate immune response is unexplored. Here the authors show that IL-4 activates the amino-acid sensing pathway in macrophages and leads to polarization of anti-inflammatory M2 macrophages via the transcription factor liver X receptor.
- Tetsuya Kimura
- , Shigeyuki Nada
- & Atsushi Kumanogoh
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Article
| Open AccessInhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium
FoxO3a signalling has limited influence over acute bacterial infection. Here the authors show that FoxO3a promotes survival of mice in response to chronic Salmonellatyphimurium infection by restraining oxidative stress and ERK signalling.
- Julie Joseph
- , Emmanuelle S. Ametepe
- & Subash Sad
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Article
| Open AccessRegulation of monocyte cell fate by blood vessels mediated by Notch signalling
Circulating Ly6Clo monocytes are thought to be derived from Ly6Chi subset. Here the authors show that Notch signalling is activated in Ly6Clocells and is required for their differentiation, and that Notch ligands that initiate this signalling are provided by a subset of endothelial cells.
- Jaba Gamrekelashvili
- , Roberto Giagnorio
- & Florian P. Limbourg
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Article
| Open AccessThe transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis
GRIP1 cooperates with the glucocorticoid receptor to repress inflammatory genes. Here the authors show that GRIP1 also controls macrophage polarization, by promoting KLF4-driven activation in response to IL-4, and that mice lacking GRIP1 in macrophages develop severe metabolic dysfunction on a high-fat diet.
- Maddalena Coppo
- , Yurii Chinenov
- & Inez Rogatsky
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Article
| Open AccessMicroglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury
Microglia and monocytes contribute to neuropathic pain states, but the precise role of the two cell types is not clear. Here Peng et al.use temporally controlled ablation of monocytes and microglia in mice to show that these cells work together to initiate neuropathic-pain like behaviour, but are less important in the maintenance phase.
- Jiyun Peng
- , Nan Gu
- & Long-Jun Wu
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Article
| Open AccessLong-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities
Understanding the heterogeneity of peritoneal macrophages is hampered by controversy over their origin and homeostasis. Here the authors show the embryonic F4/80hi population is replaced over time by self-renewing bone marrow-derived cells transitioning from F4/80lo to F4/80hi in adult mice, and that such turnover is more rapid in male mice.
- Calum C. Bain
- , Catherine A. Hawley
- & Stephen J. Jenkins
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| Open AccessHIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity
Migration to the inflamed tissue demands energy production in an increasingly hypoxic environment. Here the authors show that during migration, HIF1α-induced PDK1 uniquely adapts macrophage metabolism to mild hypoxia by promoting glycolysis while preserving cytochrome c oxidase activity.
- Hiroaki Semba
- , Norihiko Takeda
- & Issei Komuro
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Article
| Open AccessMacrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM
ABHD5 is a co-activator of lipolysis. Here the authors show that in tumour-associated macrophages ABHD5 inhibits ROS-dependent induction of C/EBPɛ, which transcriptionally activates spermidine synthase, and that blocking ABHD5 delays colorectal cancer growth in mice by inhibiting spermidine production.
- Hongming Miao
- , Juanjuan Ou
- & Houjie Liang
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Article
| Open AccessThe PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages
Elevated IL-33 levels have been correlated with metastasis and poor prognosis. Here the authors show in mouse tumour xenograft models that PDGF-BB produced by tumour cells induces IL-33 via Sox7 in tumour pericytes, and IL-33 promotes metastasis through its effects on tumour-associated macrophages.
- Yunlong Yang
- , Patrik Andersson
- & Yihai Cao
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Article
| Open AccessEpidermal Notch1 recruits RORγ+ group 3 innate lymphoid cells to orchestrate normal skin repair
In normal skin, Notch directs keratinocytes to terminally differentiate. Here the authors show that Notch1 has a wider role in skin repair; Notch1 is activated in keratinocytes after damage and drives transcription of TNFα and inflammatory chemokines, which in turn recruit ILC3s and macrophages that promote repair.
- Zhi Li
- , Tom Hodgkinson
- & Carrie A. Ambler
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| Open AccessFNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice
FDNC4 is a poorly characterized homologue of FNDC5/irisin, a myokine induced by exercise. Here the authors show that FDNC4 increases macrophage survival in growth factor deprivation, inhibits phagocytosis and transcriptional responses to M1 and M2 polarizing stimuli, and protects mice from DSS-induced colitis.
- Madeleen Bosma
- , Marco Gerling
- & Pontus Almer Boström
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| Open AccessCalcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages
Macropinocytosis can be induced in several cell types by growth factors to promote nutrient acquisition. Here the authors find that constitutive macropinocytosis, unique to dendritic cells and macrophages, requires the activity of calcium-sensing receptors.
- Johnathan Canton
- , Daniel Schlam
- & Sergio Grinstein