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Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice
Exercise could affect the immune system, but whether early-life exercise could benefit immune health in adulthood is not fully understood. Here the authors show that early-life exercise promotes epi-metabolic changes in the liver to potentially benefit immunity in older age and characterise the involvement of pipecolic acid in this process.
- Nini Zhang
- , Xinpei Wang
- & Feng Gao
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Article
| Open Access
Dysregulation of Wnt/β-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells
RORγt+ group 3 innate lymphoid cells are intimately involved in intestinal homeostasis, their dysregulation is linked to inflammatory gut diseases. Here the authors show that dysregulated Wnt/β-catenin signalling contributes to disturbed regulation of group 3 innate cells and intestinal inflammation.
- Jiacheng Hao
- , Chang Liu
- & Xiaohuan Guo
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CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer
Tumor associated macrophages (TAM) are playing an active role in tumor immune evasion in multiple cancer type. Here authors show that CD276 expression by TAMs may underpin this immune-suppressive role via promoting efferocytosis and suppressing MHC class II expression, which result in decreased CD4+ and CD8 + T cell infiltration.
- Maosheng Cheng
- , Shuang Chen
- & Liang Peng
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Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation
Gasdermin D (GSDMD) is a pore forming protein activated by inflammasome derived caspases. Here the authors characterize the function of GSDMD in mouse influenza virus infection and show that immunopathology is reduced in the absence of GSDMD and involves changes in neutrophil function.
- Samuel Speaks
- , Matthew I. McFadden
- & Jacob S. Yount
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BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Proinflammatory polarization of engineered heat-inducible macrophages reprogram the tumor immune microenvironment during cancer immunotherapy
Alternatively activated macrophages have a pivotal role in resolving inflammation but in the tumour microenvironment they are immunosuppressive. Here author show that adoptively transferred engineered macrophages harbouring a heat-inducible genetic switch can resist the polarizing effect of the tumour microenvironment, and do not only remain pro-inflammatory themselves but also re-polarise the endogenous macrophages upon controlled warming with a purpose-made device.
- Yanan Xue
- , Xiaojie Yan
- & Yuan Ping
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Antiviral responses induced by Tdap-IPV vaccination are associated with persistent humoral immunity to Bordetella pertussis
Epidemics of whooping cough caused by Bordetella pertussis have been seen and are linked to waning immunity globally. Here the authors explore responses to inactivated poliovirus (IPV) in the Tdap-IPV vaccine and show it stimulates early antiviral responses in monocytes and dendritic cells that are associated with long-lived pertussis antibody responses.
- Joshua Gillard
- , Madeleine Suffiotti
- & Dimitri A. Diavatopoulos
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NFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins
The immunobiology regulating the contribution of monocytes to severe COVID-19 immunopathology are not fully understood. Here the authors show that SARS-CoV-2 S1 and NP proteins differentially promote NLRP3/NLRC4 inflammasome activity, differentiation, and T cell-priming function of monocytes.
- Ilya Tsukalov
- , Ildefonso Sánchez-Cerrillo
- & Enrique Martin-Gayo
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Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma
Rational antibody engineering can greatly improve the clinical value of therapeutic antibodies. Here authors describe ISB 1442, a fully human bispecific antibody, consisting of two targeting modules against two different epitopes on CD38, combined with a targeting module blocking CD47 and engineered effector properties, to enhance complement dependent cytotoxicity, antibody dependent cells cytotoxicity and antibody dependent cell phagocytosis to combat multiple myeloma.
- C. Grandclément
- , C. Estoppey
- & S. Sammicheli
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Article
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ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice
Cardiac macrophage contributes to the onset of cardiac fibrosis, but the underneath mechanisms remain unclear. Here the authors show that mouse cardiac macrophages from circulating monocytes may trans-differentiate into myofibroblast under hypertensive conditions for fibrosis development, with an AKLBH5/IL11 molecular axis modulating this macrophage-to-myofibroblast transition.
- Tao Zhuang
- , Mei-Hua Chen
- & Cheng-Chao Ruan
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Article
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Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Article
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Comparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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Human cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells
Human cytomegalovirus (HCMV) is a ubiquitous pathogen associated with morbidity and mortality in the immunocompromised or immunonaive context. Here the authors show that HCMV exploits STING signalling and subverts the interferon response to support infection of monocyte derive dendritic cells.
- Bibiana Costa
- , Jennifer Becker
- & Ulrich Kalinke
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Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
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Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF
Stromal cells are key players in immune cell homeostasis. Here, the authors decipher subset-specific human stromal responses in inflammatory bowel disease and suggest that intestinal PDGFRA+CD142−/low fibroblasts guide monocyte transition to macrophages in human gut through GM-CSF.
- Egle Kvedaraite
- , Magda Lourda
- & Mattias Svensson
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NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Single-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1
Adipose beiging is a positive biological change, which is often thought to be primarily sympathetically induced. Here, the authors show that M2 macrophages can independently promote beige adipogenesis, further revealing the adipocyte transcription factor Ets1 as a negative regulator of this process.
- Suyang Wu
- , Chen Qiu
- & Xiao Han
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A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes
Natural killer (NK) cell maturation and function are regulated by multiple transcription factors (TF), but detailed molecular insights are scarce. Here the authors show that a TF, Eomes, is important for NK cell responses and cancer surveillance, in which Eomes expression is regulated by gp96 and Trim28 via the ubiquitination and degradation pathways.
- Yuxiu Xu
- , Xin Li
- & Songdong Meng
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| Open Access
Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche
The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.
- Amy Dawson
- , Martha M. Zarou
- & G. Vignir Helgason
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Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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| Open Access
A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
Mast cells serve as sentinels for mucosal infection. This study shows how mast cells can differentially detect extracellular and invasive gut bacteria, and in response tune their cytokine production to signal different levels of danger.
- Christopher von Beek
- , Anna Fahlgren
- & Mikael E. Sellin
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Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis
Whether Kupffer cells play a role in regulating the pathogenesis of fatty liver disease remains to be completely explored. Here, the authors show GPR3 activation stimulates glycolysis in Kupffer cells through GPR3-β-arrestin2-GAPDHPKM2 pathway and inhibits high-fat diet induced obesity and liver pathogenesis.
- Ting Dong
- , Guangan Hu
- & Jianzhu Chen
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| Open Access
Cebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish
Eosinophils are innate immune cells critical for protection from parasites, but their developmental origin remains under studied. Here they analyze development of eosinophils in zebrafish and find that eosinophilic lineage commitment and differentiation are regulated by the Cebp1-Cebpβ axis.
- Gaofei Li
- , Yicong Sun
- & Yiyue Zhang
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WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease
Fibroblast heterogeneity is a recognized feature in chronic kidney disease, and although fibrosis is integrant to the pathology, it is lesser known which of the fibroblast populations contribute. Here authors describe a population of proinflammatory fibroblasts, which are found in close proximity to macrophages and may facilitate their recruitment and acquisition of a FOLR2+, pathogenic phenotype.
- Camille Cohen
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity
Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade.
- Colin Y. C. Lee
- , Bethany C. Kennedy
- & Menna R. Clatworthy
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Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.
- Isaac Dean
- , Colin Y. C. Lee
- & David R. Withers
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An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life
Neutrophils play critical roles in response to infection, and the limit of available neutrophils in neonates and young infants can impact responses to infections, including sepsis. Here the authors identify that the IL-10/DEL-1 axis is involved in emergency granulopoiesis in neonates and suggest a link to sepsis survival in early life.
- Eleni Vergadi
- , Ourania Kolliniati
- & Christos Tsatsanis
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Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis
Mucins on the surface of healthy T cells limit their phagocytic uptake by macrophages. Here the authors show that upon apoptosis induction in T cells, surface mucins are cleaved and released by ADAM10 to promote efferocytosis of the apoptotic cells.
- Linnea Z. Drexhage
- , Shengpan Zhang
- & Quentin J. Sattentau
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Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents
Hantaan virus is carried and transmitted by rodents and results in asymptomatic infection, yet transmission to humans’ results in symptomatic disease and development of hemorrhagic fever with renal syndrome. Here the authors explore the disparate effects in myeloid cells from mice and humans.
- Hongwei Ma
- , Yongheng Yang
- & Fanglin Zhang
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| Open Access
Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death
Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.
- Fengxia Ma
- , Laxman Ghimire
- & Hongbo R. Luo
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The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34
Microglia could have health-promoting capacities in age-associated neuroinflammation. Here, the authors describe an autophagy and IL-34 dependent neuroprotective microglia population in the aging brain as a potential therapeutic target.
- Rasmus Berglund
- , Yufei Cheng
- & Maja Jagodic
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Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
- Shuangshuang Yang
- , Jie Xu
- & Sai-Juan Chen
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Targeted therapies of inflammatory diseases with intracellularly gelated macrophages in mice and rats
Membrane-decorated nanomedicines often suffer from reduced efficacy caused by membrane artefacts during the coating process. Here the authors show that intracellularly gelated macrophages preserve membrane properties, stay stable under ambient temperature, and show therapeutic effects in murine models of joint and lung inflammation.
- Cheng Gao
- , Qingfu Wang
- & Ruibing Wang
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| Open Access
Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity
Asthma may be exacerbated by respiratory viral infection, but the cellular and molecular mechanisms are still unclear. Here the authors show, using mouse models of asthma with influenza infection, that asthma-induced cullin5 in alveolar macrophages suppresses IFN-β production to promote neutrophilic inflammation but dampens antiviral immunity.
- Haibo Zhang
- , Keke Xue
- & Lei Sun
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Article
| Open Access
Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia
Influenza virus infection causes injury to the lung. Here, Pervizaj-Oruqaj et al. show that Plet1 expressed by lung macrophages promotes epithelial repair by boosting epithelial cell proliferation and barrier function.
- Learta Pervizaj-Oruqaj
- , Balachandar Selvakumar
- & Susanne Herold
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| Open Access
Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis
Mast cells have been shown to be involved with rheumatoid arthritis, but the mechanisms are not clear. Here using mouse models and making association with human patients, the authors show mast cells have an important function in the pathogenesis of rheumatoid arthritis, involving regulation of T cell responses and release of mast cell mediators.
- Yunxuan Lei
- , Xin Guo
- & Guangjie Chen
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Article
| Open Access
Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).
- Danfeng Dong
- , Yuzhang Du
- & Dakang Xu
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Article
| Open Access
Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (IPF) consists of lung inflammation and collagen deposition leading to reduced lung function and non-inducible mouse models are needed. Here the authors show a spontaneous mouse IPF model where Ifngr1-/-Rag2-/- mice show enhanced ILC2 activation and function along with pathology similar to IPF.
- Natsuko Otaki
- , Yasutaka Motomura
- & Kazuyo Moro
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| Open Access
Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation
Accumulation of lipid-laden macrophages in the arterial wall is a critical step in atherosclerosis. Here, the authors show that downregulation of Zeb1 in macrophages promotes lipid accumulation and atherosclerotic plaque formation while its restoration with macrophage-targeted nanoparticles reverses these effects.
- M. C. Martinez-Campanario
- , Marlies Cortés
- & Antonio Postigo
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| Open Access
Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Article
| Open Access
DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages
Although macrophages infiltrating the skeletal muscles are known to be important in muscle growth and repair, much less is known about muscle-resident macrophages. Here, the authors identify a fibro-adipogenic progenitor niche involved in the maintenance of skeletal muscle-resident macrophages.
- Farshad Babaeijandaghi
- , Nasim Kajabadi
- & Fabio M. V. Rossi
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| Open Access
Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Difficulties can be encountered when translating research between cells from animals and humans because of gene expression differences. Here the authors perform an integrative transcriptomic analysis from human and mouse neutrophils and identify a core inflammation program shared across inflamed contexts.
- Nicolaj S. Hackert
- , Felix A. Radtke
- & Ricardo Grieshaber-Bouyer
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Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling
Paneth cell metaplasia (PCM) typically arises in diseases intrinsic to the gastrointestinal tract; however, whether extra intestinal diseases can trigger PCM and the mechanistic pathway by which PCM develops is unknown. Herein, the authors show in an inducible murine model of chronic myelogenous leukaemia that a systemic inflammatory state can trigger IL-33- mediated IL-9 production that leads to small intestinal remodelling and PCM.
- Chengyin Yuan
- , Aditya Rayasam
- & William R. Drobyski
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| Open Access
Intrinsic factors and CD1d1 but not CD1d2 expression levels control invariant natural killer T cell subset differentiation
Invariant natural killer T (NKT) cells are defined into subset based on transcription expression and cytokine production, but differences in the subset distributions of these cells are seen between inbred mouse strains. Here the authors show that CD1d mediated TCR signals along with intrinsic signals impact this strain specific difference in the composition of the NKT cell compartment.
- Ludivine Amable
- , Luis Antonio Ferreira Martins
- & Kamel Benlagha
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| Open Access
Dermis resident macrophages orchestrate localized ILC2 eosinophil circuitries to promote non-healing cutaneous leishmaniasis
Tissue resident macrophages are intricately involved in homeostatic processes but also in tissue repair. Here Lee and colleagues show dermis-resident macrophages are a source of thymic stromal lymphopoietin and CCL24, which act on type 2 innate lymphoid cells and eosinophils respectively, to maintain their M2 properties and promote non-healing cutaneous leishmaniasis.
- Sang Hun Lee
- , Byunghyun Kang
- & David L. Sacks
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| Open Access
Protective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis
During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin α5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.
- Ruoshui Li
- , Bijun Chen
- & Nikolaos G. Frangogiannis
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| Open Access
The transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure
Acute hypoxemic respiratory failure (AHRF) and the associated lung immune cell features are not well understood. Here the authors use CITE-Seq to analyse the transcriptomic and phenotypic profile of lung and blood cells from a longitudinal cohort of patients with AHRF to identify gene signatures and cell surface proteins associated with disease severity.
- Eric D. Morrell
- , Sarah E. Holton
- & Carmen Mikacenic
Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant