Featured
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Article |
Necroptosis blockade prevents lung injury in severe influenza
A newly developed RIPK3 inhibitor blocks necroptosis of lung cells, reduces lung inflammation and prevents mortality in a mouse model of influenza A virus infection.
- Avishekh Gautam
- , David F. Boyd
- & Siddharth Balachandran
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Perspective |
The power and potential of mitochondria transfer
The mechanisms by which mitochondria are transferred between cells and how intercellular mitochondria transfer regulates physiological processes and disease pathogenesis are discussed.
- Nicholas Borcherding
- & Jonathan R. Brestoff
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Article |
Structural mechanisms for regulation of GSDMB pore-forming activity
The cryo-EM structure of the GSDMB pore reveals mechanisms by which GSDMB pore-forming activity is regulated by pathogenic bacteria and mRNA splicing.
- Xiu Zhong
- , Huan Zeng
- & Jingjin Ding
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Article
| Open Access
ADAR1 averts fatal type I interferon induction by ZBP1
ADAR1 prevents Z-RNA-dependent activation of pathogenic type I interferon responses by ZBP1, whose activity may contribute to pathology in type I interferonopathies with ADAR1 mutations.
- Huipeng Jiao
- , Laurens Wachsmuth
- & Manolis Pasparakis
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Article |
ADAR1 mutation causes ZBP1-dependent immunopathology
The autoinflammatory pathology associated with alteration of the ZBD domain of the RNA-editing enzyme ADAR1 is driven by signalling that is dependent on the nucleotide sensor ZBP1.
- Nicholas W. Hubbard
- , Joshua M. Ames
- & Andrew Oberst
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Article |
ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation
In addition to its role in suppressing MDA5 and PKR activation, ADAR1 is a negative regulator of ZPB1-mediated apoptosis and necroptosis, providing insights into the pathology of Aicardi–Goutières syndrome.
- Richard de Reuver
- , Simon Verdonck
- & Jonathan Maelfait
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Article |
Caspase-7 activates ASM to repair gasdermin and perforin pores
Caspase-7 cleaves and activates acid sphingomyelinase (ASM), which promotes the repair of gasdermin pores and thereby delays pore-driven lysis to allow other processes such as extrusion or apoptosis to occur before cell death.
- Kengo Nozaki
- , Vivien I. Maltez
- & Edward A. Miao
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Article |
ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis
A small molecule can bypass the RNA-editing enzyme ADAR1 to directly activate the Z-form nucleic acid sensor ZBP1, induce necroptosis in tumour fibroblasts and reverse resistance to immune checkpoint blockade in mouse models of melanoma.
- Ting Zhang
- , Chaoran Yin
- & Siddharth Balachandran
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Article |
Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes
Transcriptomic, genetic and pharmacological analysis identifies SLC7A11 as an inhibitor of efferocytosis in dendritic cells, and increased expression of this protein may cause slower wound healing in diabetes.
- Sophia Maschalidi
- , Parul Mehrotra
- & Kodi S. Ravichandran
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Article |
Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes
Group A Streptococcus secretes a protease, SpeB, that directly cleaves and activates gasdermin A to induce pyroptosis of infected keratinocytes, demonstrating a role for gasdermin A in immune defence against invasive microorganisms.
- Doris L. LaRock
- , Anders F. Johnson
- & Christopher N. LaRock
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Article |
Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11
This study reports the identification of a new post-translational modification, termed ADP riboxanation, which is mediated by the Shigella effector OspC3 and inactivates the cytosolic LPS sensing pathway of caspase-4 and caspase-11.
- Zilin Li
- , Wang Liu
- & Feng Shao
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Article |
Cooperative epithelial phagocytosis enables error correction in the early embryo
Mechanical load-sharing enables the long-range cooperative uptake of apoptotic cells by multiple epithelial cells; and clearance of these apoptotic cells facilitates error correction, which is necessary for developmental robustness and survival of the embryo.
- Esteban Hoijman
- , Hanna-Maria Häkkinen
- & Verena Ruprecht
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Article |
Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation
Analyses of mouse models of inflammation suggest some chronic inflammatory conditions may result from Z-DNA-binding protein 1 sensing endogenous Z-form nucleic acids—such as those of endogenous retroelements—through its Zα domains.
- Huipeng Jiao
- , Laurens Wachsmuth
- & Manolis Pasparakis
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Article |
Metabolites released from apoptotic cells act as tissue messengers
Apoptotic cells communicate with neighbouring cells by the regulated release of specific metabolites, and a cocktail of select apoptotic metabolites reduces disease severity in mouse models of inflammatory arthritis and lung transplant rejection.
- Christopher B. Medina
- , Parul Mehrotra
- & Kodi S. Ravichandran
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Article |
Gasdermin E suppresses tumour growth by activating anti-tumour immunity
The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.
- Zhibin Zhang
- , Ying Zhang
- & Judy Lieberman
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Article |
A bioorthogonal system reveals antitumour immune function of pyroptosis
In mouse models of cancer, a biorthogonal chemical system based on desilylation catalysed by phenylalanine trifluoroborate enables the controlled release of gasdermin to induce pyroptosis selectively in tumour cells
- Qinyang Wang
- , Yupeng Wang
- & Zhibo Liu
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Article |
A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1
A dominantly inherited human autoinflammatory disease caused by mutations in RIPK1 is identified, and RIPK1 mutations that prevent caspase-8 cleavage sensitize cells to apoptosis, necroptosis and inflammation.
- Panfeng Tao
- , Jinqiao Sun
- & Qing Zhou
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Article |
Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis
The enzymatic activity of caspase-8 controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood in mice.
- Melanie Fritsch
- , Saskia D. Günther
- & Hamid Kashkar
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Article |
Activity of caspase-8 determines plasticity between cell death pathways
Alternative cell death pathways are revealed in the absence of caspase-8-dependent apoptosis and MLKL-dependent necroptosis.
- Kim Newton
- , Katherine E. Wickliffe
- & Vishva M. Dixit
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Letter |
Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release
Distinct transcriptional programs are activated during different stages of apoptotic cell engulfment, including a unique program of genes coding for solute carrier proteins and enzymes in the glycolytic pathway.
- Sho Morioka
- , Justin S. A. Perry
- & Kodi S. Ravichandran
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Letter |
OTULIN limits cell death and inflammation by deubiquitinating LUBAC
OTULIN, which removes ubiquitin chains deposited by LUBAC, promotes LUBAC activity by preventing its auto-ubiquitination, thereby supporting normal mouse embryo development and preventing pro-inflammatory cell death in adult mice.
- Klaus Heger
- , Katherine E. Wickliffe
- & Vishva M. Dixit
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Letter |
Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs
Apoptotic intestinal epithelial cells can be sampled by lamina propria phagocytes, leading to distinct phagocyte-type-specific anti-inflammatory gene signatures and dendritic-cell-mediated induction of regulatory T cells.
- Ryan J. Cummings
- , Gaetan Barbet
- & J. Magarian Blander
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Letter |
RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation
The enzyme RIPK1 functions through its RHIM domain to prevent ZBP1-mediated activation of RIPK3–MLKL-dependent necroptosis, thus preventing perinatal lethality and skin inflammation in adult mice.
- Juan Lin
- , Snehlata Kumari
- & Manolis Pasparakis
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Letter |
Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation
Macrophage-derived insulin-like growth factor enhances the uptake of microvesicles by non-professional phagocytes, such as airway epithelial cells and fibroblasts, thereby dampening tissue inflammation.
- Claudia Z. Han
- , Ignacio J. Juncadella
- & Kodi S. Ravichandran
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Letter |
TAM receptors regulate multiple features of microglial physiology
Microglial phagocytosis is required for neurogenic niche maintenance and response to injury; the TAM kinases Mer and Axl are expressed by microglia in the adult CNS, and mediate the clearance of apoptotic cells from the niche.
- Lawrence Fourgeaud
- , Paqui G. Través
- & Greg Lemke
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Article |
Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation
The authors define molecular mechanisms by which distinct domains of the ubiquitin editing enzyme A20 contribute to the regulation of inflammation and cell death.
- Ingrid E. Wertz
- , Kim Newton
- & Vishva M. Dixit
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Article |
Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
CRISPR-Cas9 genome-editing screens identify gasdermin D as a substrate for inflammatory caspases, and its N-terminal cleavage fragment, as well as the equivalent regions in other gasdermins, is shown to be capable of inducing pyroptosis.
- Jianjin Shi
- , Yue Zhao
- & Feng Shao
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Letter |
RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis
This study provides evidence for a critical role of RIPK1 in suppressing caspase-8-mediated cell death and maintaining intestinal homeostasis independently of its kinase activity.
- Nozomi Takahashi
- , Lars Vereecke
- & Peter Vandenabeele
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Letter |
RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis
RIPK1 is shown to have a crucial role—independent of its known kinase function—in suppressing epithelial cell apoptosis and necroptosis in mice, thereby regulating homeostasis and preventing inflammation in barrier tissues.
- Marius Dannappel
- , Katerina Vlantis
- & Manolis Pasparakis
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Letter |
Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains
Several death-domain-containing proteins are directly inactivated by the enteropathogenic Escherichia coli type III secretion system effector NleB; NleB functions as an N-acetylglucosamine transferase that modifies a conserved death domain arginine residue, blocking the receptor–adapter interaction.
- Shan Li
- , Li Zhang
- & Feng Shao
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Letter |
Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2
Genetic analysis of breakthrough infections in people vaccinated against HIV-1 show that vaccine efficacy increased by up to 80% against viruses carrying two mutations in Env V2, but also raises the possibility of population-level adaptation to the vaccine.
- Morgane Rolland
- , Paul T. Edlefsen
- & Jerome H. Kim
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Letter |
NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens
The Nod-like receptor family member NLRP6 is characterized and shown to be a negative regulator of inflammatory signalling, dampening host responses against bacterial infections and impeding bacterial clearance.
- Paras K. Anand
- , R. K. Subbarao Malireddi
- & Thirumala-Devi Kanneganti
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Research Highlights |
Good microbes fight bad
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Letter |
Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice
Consumption of a diet high in milk-derived fat is shown to increase the abundance of sulphite-reducing bacteria by altering bile composition, leading to inflammation and colitis in genetically susceptible mice.
- Suzanne Devkota
- , Yunwei Wang
- & Eugene B. Chang
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News & Views Forum |
Allergy challenged
An article suggesting that allergic responses may not be an accident of an off-target immune system, but rather a deliberate defence against potential harm, provokes the question of whether our understanding of allergy needs an overhaul. Immunologists provide their opinions. See Perspective p.465
- David Artis
- , Rick M. Maizels
- & Fred D. Finkelman
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News & Views |
Recognition of a unique partner
The mammalian immune system can fight a myriad of pathogens. In part, this involves a superfamily of cytoplasmic receptors that dictate assembly of specific pro-inflammatory inflammasome complexes. See Letters p.592 & p.596
- Denise M. Monack
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Letter |
FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
- Patrick-Simon Welz
- , Andy Wullaert
- & Manolis Pasparakis
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News & Views |
Host and microbes in a pickle
Metabolic disorders such as obesity are characterized by long-term, low-grade inflammation. Under certain conditions, the resident microorganisms of the gut might contribute to this inflammation, resulting in disease.
- Ping Li
- & Gökhan S. Hotamisligil
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News & Views |
Culprits with evolutionary ties
The cellular organelles we know as mitochondria are thought to have originated as symbiotic bacteria. Indeed, the two use common mechanisms to trigger innate immune responses to injury and infection, respectively.
- Carolyn S. Calfee
- & Michael A. Matthay
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News |
How the cell's powerhouses turn deadly
Mitochondria can trigger a lethal immune response after injuries.
- Heidi Ledford
Brain endothelial GSDMD activation mediates inflammatory BBB breakdown