Featured
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| Open AccessSingle-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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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessMitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity
Stress-independent autophagy is less understood than stress-induced autophagy and is important for thymic self-tolerance. Here the authors show that a mitochondrial protein C15ORF48 is important for stress-independent autophagy and alters glutathione metabolism and C15orf48 knockout mice develop autoimmunity and changes to thymic epithelial cells.
- Yuki Takakura
- , Moeka Machida
- & Noritaka Yamaguchi
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Article
| Open AccessA cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis
Viruses have evolved specific mechanisms to reduce programmed cell death in order to prolong survival. Here the authors show a mouse cytomegalovirus (MCMV) encoded protein that inhibits pyroptosis, proinflammatory cytokine release and the assembly of inflammasomes.
- Yingqi Deng
- , Eleonore Ostermann
- & Wolfram Brune
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Article
| Open AccessGasdermin 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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Article
| Open AccessIKKε and TBK1 prevent RIPK1 dependent and independent inflammation
TBK1 and IKKε are involved in the regulation of a range of cellular and inflammatory processes. Here Eren and colleagues discern a role for IKKε in preventing RIPK1-dependent and RIPK1-independent inflammation in mice lacking TBK1 kinase activity.
- Remzi Onur Eren
- , Göksu Gökberk Kaya
- & Manolis Pasparakis
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Article
| Open AccessIL-21R-STAT3 signalling initiates a differentiation program in uterine tissue-resident NK cells to support pregnancy
Uterine natural killer (NK) cells support tissue homeostasis in the uterus during pregnancy, but it is not fully known how they differentiate into potentially cytotoxic effector cells while avoiding tissue damage. Here authors show that Il21 receptor signalling via STAT3 activation governs their differentiation, while an apoptotic cell death program ensures that harm is limited.
- Mengwei Han
- , Luni Hu
- & Chao Zhong
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Article
| Open AccessAn innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2
Pathogens often persist within granulomas which form to control infection. Here, Harvest et al describe an innate granuloma that eradicates a ubiquitous environmental pathogen without inducing adaptive immunity.
- Carissa K. Harvest
- , Taylor J. Abele
- & Edward A. Miao
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Article
| Open AccessPlant immunity suppression by an exo-β-1,3-glucanase and an elongation factor 1α of the rice blast fungus
Fungal cell walls release β-1,3-glucan fragments that trigger plant immunity. Here, the authors show that a glucanase (Ebg1) of the blast fungus Magnaporthe oryzae suppresses plant immunity by hydrolyzing β-1,3-glucan. At the same time, Ebg1 induces plant immune responses that are dampened by a fungal protein that interacts with Ebg1.
- Hang Liu
- , Xunli Lu
- & You-Liang Peng
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Article
| Open AccessA cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses
Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.
- Zhigui Zuo
- , Hao Yin
- & Qinyang Wang
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Article
| Open AccessAhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
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Article
| Open AccessLongitudinal high-dimensional analysis identifies immune features associating with response to anti-PD-1 immunotherapy
Immune checkpoint blockade therapy improved the survival rates of non-small cell lung cancer but only a proportion of patients benefit. Here authors follow the humoral and cellular immunological parameters of patients undergoing anti-PD1 therapy longitudinally and find that levels and functional properties of cytotoxic T cells, and especially CD8+CD101hiTIM3+ cells determine the response.
- Elaine Lai-Han Leung
- , Run-Ze Li
- & Liang Liu
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Article
| Open AccessExecutioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis
During apoptosis, mitochondrial outer membrane permeabilization results in cytosolic mitochondrial RNA (mtRNA). Here, the authors demonstrate that caspase-3/7 inhibition promotes a cytosolic mtRNA-driven Type I interferon response via MDA5/MAVS/IRF3, increasing the immunogenicity of chemotherapy-induced apoptosis.
- Shane T. Killarney
- , Rachel Washart
- & Kris C. Wood
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Article
| Open AccessGSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis
Macrophages have been shown to have an important function in atherosclerosis. Here the authors show that, in human atherosclerotic plaques and mouse models, GSDME and pyroptosis promote atherosclerosis and inhibition of these pathways could reduce pathology associated with atherosclerotic disease.
- Yuanyuan Wei
- , Beidi Lan
- & Yue Wu
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Article
| Open AccessOxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus
Systemic lupus erythematosus is characterised by the generation of antibodies targeting DNA and nuclear antigens. Here, the authors show that oxidised mitochondrial DNA induces gasdermin D oligomerization and promotes pore formation in neutrophils from patients with SLE.
- Naijun Miao
- , Zhuning Wang
- & Jing Wang
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Article
| Open AccessExpansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis
The induction of immunogenic cell death (ICD) can potentiate antitumour immunity. Here the authors show that USP18, a negative regulator of IFN signaling protects cancer cells from ICD by suppressing the expression of canonical and non-canonical IFN-stimulated genes.
- Kei-ichiro Arimoto
- , Sayuri Miyauchi
- & Dong-Er Zhang
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Article
| Open AccessA genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis
Efferocytosis describes the engulfment and clearance of apoptotic cells by phagocytes. Here the authors identify in primary mouse macrophage WDFY3 as a regulator for efferocytosis, in which c-terminal WDFY3 is sufficient to modulate degradation while full-length WDFY3 is required to modulate the uptake of apoptotic cells.
- Jianting Shi
- , Xun Wu
- & Hanrui Zhang
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Article
| Open AccessIL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis
The beta-glucan receptor EphA2 is known to maintain mucosal immunity. Here, its role in modulating renal immunopathology via IL-23 signalling and ferroptotic cell death during candidiasis is characterised.
- Nicolas Millet
- , Norma V. Solis
- & Marc Swidergall
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Article
| Open AccessCancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity
Inducing ferroptosis of tumour cells is a promising therapeutic approach in cancer. Authors show here that on the other hand, cells dying via ferroptosis are less immunogenic than necroptotic cells, they inhibit maturation and antigen cross-presentation of dendritic cells, hence lessen the anti-tumour immune response.
- Bartosz Wiernicki
- , Sophia Maschalidi
- & Peter Vandenabeele
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Article
| Open AccessPEBP balances apoptosis and autophagy in whitefly upon arbovirus infection
Arbovirus has co-evolved with its insect vector, enabling efficient and persistent transmission by vectors. Here, the authors reveal an immune homeostatic mechanism shaped by apoptosis and autophagy that facilitates arbovirus preservation within its whitefly vector.
- Shifan Wang
- , Huijuan Guo
- & Yucheng Sun
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Article
| Open AccessTNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models
Expansion of synovial fibroblast is associated with rheumatoid arthritis (RA) progression, but how this expansion is regulated is still not clear. Here the authors use a mouse RA model, single cell RNA sequencing and in vitro analyses to show that inducing ferroptosis and suppressing TNF signaling reduce fibroblast numbers and ameliorate experimental arthritis.
- Jiao Wu
- , Zhuan Feng
- & Ping Zhu
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Article
| Open AccessTargeting necroptosis in muscle fibers ameliorates inflammatory myopathies
Polymyositis (PM) is a chronic inflammatory myopathy characterized by progressive muscle weakness. Here the authors showed that muscle fibers in PM undergo necroptosis and aggravate inflammation via releasing pro-inflammatory molecules such as HMGB1.
- Mari Kamiya
- , Fumitaka Mizoguchi
- & Shinsuke Yasuda
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Article
| Open AccessMesenchymal stromal cell apoptosis is required for their therapeutic function
Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.
- Swee Heng Milon Pang
- , Joshua D’Rozario
- & Tracy S. P. Heng
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Article
| Open AccessPhosphoproteome profiling uncovers a key role for CDKs in TNF signaling
Tumor necrosis factor (TNF) has various effects on phosphorylation-mediated cellular signaling. Combining phosphoproteomics, subcellular localization analyses and kinase inhibitor assays, the authors provide systems level insights into TNF signaling and identify modulators of TNF-induced cell death.
- Maria C. Tanzer
- , Isabell Bludau
- & Matthias Mann
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Article
| Open AccessOTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
OTULIN is a deubiquitinase for linear ubiquitin chains. Here the authors show, using genetic mouse models and single-cell RNA-sequencing, that deficiency of OTULIN in keratinocytes causes skin inflammation and verrucous carcinoma via the induction of keratinocyte death, thereby implicating a function of OTULIN in keratinocyte homeostasis.
- Esther Hoste
- , Kim Lecomte
- & Geert van Loo
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Article
| Open AccessOTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
OTULIN is a negative regulator of linear ubiquitination, and its deficiency in human causes multi-organ inflammations including the skin. Here the authors show, by combining various genetic tools with epidermis-specific Otulin knockout mice, that Otulin suppresses skin inflammation predominantly by inhibiting RIPK1-mediated keratinocytes necroptosis.
- Hannah Schünke
- , Ulrike Göbel
- & Manolis Pasparakis
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Article
| Open AccessTet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
There are dynamic interactions between immune cells and β cells that lead to β cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of β cells in mice.
- Jinxiu Rui
- , Songyan Deng
- & Kevan C. Herold
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Article
| Open AccessPerfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome
The double-stranded DNA receptor AIM2 is able to sense the environmental pollutant perfluorooctane sulfonate, a prototypical perfluoro-alkyl substrate. Activation of the AIM2 pathway leads to inflammation and tissue damage via IL-1β secretion and pyroptosis of affected innate immune cells.
- Li-Qiu Wang
- , Tao Liu
- & Jun Cui
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Article
| Open AccessPD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition
The mechanistic detail of how PD-1 inhibits T cell activation is lacking. Here, the authors show PD-1 suppresses the cooperative TCR–pMHC–CD8 interaction by inhibiting TCR proximal signalling.
- Kaitao Li
- , Zhou Yuan
- & Cheng Zhu
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Article
| Open AccessCoding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity
Mito-SEPs are small peptides that can modulate oxidative metabolism in mitochondria. Here the authors show that C15ORF48 encodes a mito-SEP, MOCCI, capable of altering mitochondria respiration to suppress inflammation, while C15ORF48 3’ untranslated region also contains a miRNA, miR-147b, that synergizes with MOCCI to modulate host anti-viral responses.
- Cheryl Q. E. Lee
- , Baptiste Kerouanton
- & Lena Ho
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Article
| Open AccessType I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
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Article
| Open AccessProteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells
Targeting regulatory T cells (Treg) represents a therapeutic option to abrogate tumor-associated immune suppression. Here the authors show that pharmacological degradation of BCL-XL preferentially induces apoptosis of tumor-infiltrating Treg, promoting CD8 T cell activation and anti-tumor immune responses in preclinical cancer models.
- Ryan Kolb
- , Umasankar De
- & Weizhou Zhang
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Article
| Open AccessZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1
Yersiania YopJ protein has been shown to drive caspase-8-mediated pyroptosis. Here the authors show a precise mechanism of this non-canonical cell death pathway that is controlled by a TRIF-dependent complex of FADD, RIPK1, caspase-8 and ZBP1.
- Hayley I. Muendlein
- , Wilson M. Connolly
- & Alexander Poltorak
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Article
| Open AccessTipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death
Most chemotherapeutic agents, including gemcitabine, do not elicit immunogenic cell death, a phenomenon associated with the release of damage-associated molecule patterns (DAMPs). Here, the authors show that gemcitabine-treated dying cancer cells express hallmark DAMPs but their immunogenic properties are hindered by the concomitant release of the inhibitory DAMP PGE2.
- K. Hayashi
- , F. Nikolos
- & K. S. Chan
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Article
| Open AccessThe CCR4–NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression
The CCR4-NOT complex catalyzes mRNA deadenylation and hence regulates protein translation. Here the authors show that CNOT3 regulation of this complex is needed for positive selection of thymocytes via a mechanism involving inhibition of pro-apoptotic gene expression.
- Taku Ito-Kureha
- , Takahisa Miyao
- & Tadashi Yamamoto
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Article
| Open AccessDurable and controlled depletion of neutrophils in mice
Anti-Ly6G or ant-Gr1 antibodies are commonly used to deplete neutrophils in vivo. Here the authors provide mechanistic insight into why these approaches may not specifically or durably reduce the number of neutrophils in mice, and also present a new method that overcomes these limitations to have potentially wide applicability in experimental studies.
- Gael Boivin
- , Julien Faget
- & Etienne Meylan
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Article
| Open AccessCaspase-11 signaling enhances graft-versus-host disease
An increasing number of inflammatory pathologies is associated with IL-1 production downstream of caspases 1 and 11. Here the authors show that graft-versus-host-disease (GvHD) is diminished in mice with genetic or pharmacological ablation of caspase-11, and provide mechanistic insights into the signals leading to caspase-11 activation in GvHD.
- Yanyan Lu
- , Ran Meng
- & Ben Lu
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Article
| Open AccessModulation of autoimmune pathogenesis by T cell-triggered inflammatory cell death
Many forms of autoimmune disorder involve abnormal T cell functions, but how this versatility is achieved is not fully clear. Here the authors show that Sharpin-deficient Treg cells induce the death of local keratinocytes via multiple programmed cell death and innate inflammation to cause skin inflammation similar to cpdm mice with genetic deletion of Sharpin.
- Katsuhiro Sasaki
- , Ai Himeno
- & Kazuhiro Iwai
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Article
| Open AccessContemporaneous 3D characterization of acute and chronic myocardial I/R injury and response
Detailed characterization of cardiac damage following ischemia/reperfusion injury and detection of occurring inflammatory responses is important for the development of new therapeutic concepts. Here the authors present a method for the three-dimensional investigation of acute and chronic cardiac injury responses using light sheet fluorescence microscopy.
- Simon F. Merz
- , Sebastian Korste
- & Matthias Totzeck
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Review Article
| Open AccessCompetition for nutrients and its role in controlling immune responses
Immune cells adapt distinct metabolic strategies to accommodate specific functions associated with cell types or differentiation stages. Here in this review the authors discuss the nutrients, sensors, and mediators of such a metabolic adaption in nutrient-limiting immune microenvironments such as tumors or infections.
- Nidhi Kedia-Mehta
- & David K. Finlay
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Article
| Open AccessSerine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
RIPK1 kinase activity is known to transduce a death signal, but the molecular mechanisms that normally prevent RIPK1 activation are unclear. Here, the authors report that IKK-mediated phosphorylation on RIPK1 Ser25 directly represses its enzymatic activity and thus RIPK1-dependent cell death.
- Yves Dondelinger
- , Tom Delanghe
- & Mathieu J. M. Bertrand
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Article
| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessCrizotinib-induced immunogenic cell death in non-small cell lung cancer
Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.
- Peng Liu
- , Liwei Zhao
- & Guido Kroemer
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Article
| Open AccessTRADD regulates perinatal development and adulthood survival in mice lacking RIPK1 and RIPK3
Programmed cell death regulates early development but how various factors (for example, TRADD, FADD and RIPKs) regulate this is unclear. Here, the authors show that a single allele of Tradd is essential for survival, when both Ripk3 and Ripk1 are knocked out in mice, and RIPK1 protects thymocytes from TNF-induced apoptosis.
- John P. Dowling
- , Mohamed Alsabbagh
- & Jianke Zhang
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Article
| Open AccessApoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis
The enterotoxins TcdA and TcdB induce cytotoxicity of epithelial cells during Clostridium difficile infection. Here the authors show that bacterial induced epithelial cell death occurs via activation of caspases 3 and 7, resulting in apoptotic cell death.
- Pedro H. V. Saavedra
- , Linyan Huang
- & Mohamed Lamkanfi
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Article
| Open AccessA FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs
Necroptotic cells activate MLKL and release inflammatory DAMPs, although the underlying regulatory mechanisms of this process are poorly understood. Here, Murai et al. develop a necroptosis-specific FRET sensor (SMART) that monitors MLKL membrane translocation to identify two modes of DAMP release.
- Shin Murai
- , Yoshifumi Yamaguchi
- & Hiroyasu Nakano
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Article
| Open AccessThe fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes
Phagocytic cells of the innate immune system play critical roles in defence against invading pathogens including the opportunistic pathogen Candida albicans. Here the authors show that C. albicans derived Candidalysin in addition to being a cell-damaging toxin to mononuclear phagocytes is a trigger of NLRP3 inflammasome activation in these cells.
- Lydia Kasper
- , Annika König
- & Bernhard Hube
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Article
| Open AccessRegulation of the terminal maturation of iNKT cells by mediator complex subunit 23
Invariant Natural Killer T cells (iNKT) rapidly exert effector functions upon activation, but the mechanisms of their functional maturation remain to be determined. Here, Xu and colleagues show that the mediator subunit Med23 is a transcriptional regulator controlling iNKT cell terminal maturation.
- Yu Xu
- , Yang Sun
- & Xiaolong Liu
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Article
| Open AccessChromatin regulates IL-33 release and extracellular cytokine activity
Interleukin-33 (IL-33) can be released as a cytokine or transported into the nucleus, but the significance of this nuclear shuttling is not fully understood. Here the authors show that chromatin-binding of IL-33 alters, unexpectedly, the activity of IL-33 both in alarmin release kinetics and receptor signaling capacity.
- Jared Travers
- , Mark Rochman
- & Marc E. Rothenberg