Featured
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Article
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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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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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Structural basis for the oligomerization-facilitated NLRP3 activation
NLRP3 is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Here, the authors determined Cryo-EM structures of human NLRP3 in its closed and open states, elucidating the mechanism of NLRP3 inflammasome activation.
- Xiaodi Yu
- , Rosalie E. Matico
- & Sujata Sharma
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Pathogenic 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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VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation
Acquired mutations of the gene UBA1 occurring in myeloid cells that result in the expression of impaired isoforms of the enzyme E1 have been described in patients with a severe adult onset auto-inflammatory syndrome called VEXAS. Here the authors profile patients with UBA1 mutations presenting with or without VEXAS disease and show VEXAS disease is characterized by inflammasome activation and monocyte dysregulation.
- Olivier Kosmider
- , Céline Possémé
- & Benjamin Terrier
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A 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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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
Acetylation is required for full activation of the NLRP3 inflammasome
The NLRP3 inflammasome is activated in two steps, priming and assembly, in response to endogenous, microbial, and other environmental danger signals. Here authors show that the assembly step is regulated by acetylation, and inhibition of this post-translational modification prevents full activation of the inflammasome.
- Yening Zhang
- , Ling Luo
- & Kai Zhao
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Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity
Bacterial infection of immune cells can result in engagement of different immunological pathways. Here the authors show that a Pseudomonas aeruginosa type three secretion system exoenzyme is linked to the differential selection of inflammasome usage between macrophages and neutrophils.
- Martin S. Minns
- , Karl Liboro
- & Eric Pearlman
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Article
| Open Access
IL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation
The turnover of interleukin-1β, a cytokine that plays important roles in both physiologic and pathologic inflammatory processes, is regulated by proteolytic maturation of the pro-form and by ubiquitin-mediated degradation. Here authors identify the specific ubiquitin E3 ligases that form an active complex with UBE2L3, a ubiquitin conjugating enzyme, that target pro-IL-1β for proteasomal breakdown.
- Vishwas Mishra
- , Anna Crespo-Puig
- & Avinash R. Shenoy
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Article
| Open Access
Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon
Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.
- Tristram A. J. Ryan
- , Alexander Hooftman
- & Luke A. J. O’Neill
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A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells
NLRP3 inflammasomes trigger release of IL-1 to promote tissue injury. Here, Li et al identify a ZFYVE21-Rubicon-RNF34 (ZRR) signaling complex localizing to endosomes and modulating complement-mediated inflammasome activity in vitro and in vivo.
- Xue Li
- , Quan Jiang
- & Dan Jane-wit
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Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model
The immune response has been suggested to be involved in the pathology of Ménière’s disease. Here the authors implicate serum glucocorticoid-inducible kinase 1 as a regulator of the NLRP3 inflammasome and link to macrophage function in a model of Ménière’s disease pathology.
- Dao-Gong Zhang
- , Wen-Qian Yu
- & Hai-Bo Wang
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Article
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Microbiota-derived acetate enhances host antiviral response via NLRP3
The NLRP3 inflammasome plays a pivotal role in clearing viral respiratory infection, but the molecular mechanism is not fully known. Here authors show that acetate, produced by gut bacteria, may enhance NLRP3-mediated type I interferon production following influenza infection in mice.
- Junling Niu
- , Mengmeng Cui
- & Guangxun Meng
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Article
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CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes
The chemokine, CXCL4, is proposed to enhance Toll-like receptor (TLR) signaling by facilitating TLR ligand import. Here the authors show that CXCL4 also synergizes with TLR8 to promote the activation of TBK1 and IKKε and induce epigenetic remodeling of relevance inflammatory genes to enhance inflammatory responses in human monocytes.
- Chao Yang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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| Open Access
TH17 cells promote CNS inflammation by sensing danger signals via Mincle
Mincle is a pattern recognition receptor that senses danger signals in innate immune cells. Here authors show in an experimental autoimmune encephalomyelitis mouse model that tissue damage triggers Mincle signaling on inflammatory helper T cells, leading to inflammasome-mediated IL-1β production and reinforced inflammation.
- Quanri Zhang
- , Weiwei Liu
- & Xiaoxia Li
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CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT
Pseudomonas aeruginosa secretes the toxin ExoT, which is important for pathogenesis. Here, the authors show that ExoT inhibits NLRC4-dependent inflammatory responses during wound infection.
- Mohamed F. Mohamed
- , Kajal Gupta
- & Sasha H. Shafikhani
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| Open Access
The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages
Inflammasome regulation is not fully understood. Here the authors show that the early endosomal APPL1-Rab5 axis removes damaged mitochondria and then restricts the inflammasome response in macrophages, alleviating the inflammatory diseases.
- Kelvin Ka Lok Wu
- , KeKao Long
- & Kenneth King Yip Cheng
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| Open Access
NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly
Nlrp3 inflammasome activation requires Nek7 recruitment to drive ASC speck formation. Here the authors show how Nlrp3 phosphorylation events control this Nek7 recruitment.
- Tingting Niu
- , Charlotte De Rosny
- & Bénédicte F. Py
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Chlamydia evasion of neutrophil host defense results in NLRP3 dependent myeloid-mediated sterile inflammation through the purinergic P2X7 receptor
Myeloid cells are implicated in the innate immune and inflammatory response during infection with Chlamydia trachomatis. Here the authors show the evasion of the neutrophil response to infection and concomitant induction of sterile immunity via the purinergic P2X7 receptor.
- Chunfu Yang
- , Lei Lei
- & Harlan D. Caldwell
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Article
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TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation
Post-translational modifications are important regulators of NLRP3 inflammasome activity. Here the authors show that the E3 ligase TRIM28 can SUMOylate NLRP3, thereby limiting its proteasomal degradation and increasing NLRP3 inflammasome activity.
- Ying Qin
- , Qi Li
- & Wei Zhao
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Article
| Open Access
SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation
SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.
- Pan Pan
- , Miaomiao Shen
- & Jianguo Wu
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Article
| Open Access
Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis
The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.
- Lindsey Mayes-Hopfinger
- , Aura Enache
- & Emad S. Alnemri
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Article
| Open Access
Perfluoroalkyl 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 Access
The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation
Hyperactivation of inflammasome-induced IL-1β can cause immunopathology and is a feature of autoinflammatory diseases. Here, the authors show how ubiquitination of IL-1β limits its activity by targeting it for proteasomal degradation and preventing its cleavage by caspase-1.
- Swarna L. Vijayaraj
- , Rebecca Feltham
- & James E. Vince
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Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
NLRP1 and CARD8 are two recently described sensor proteins for the human inflammasome complex. Here, the authors present the cryo-EM CARD filament structures of the NLRP1 and CARD8 activating domains, which reveal how NLRP1 and CARD8 discriminate between ASC and pro-caspase-1. They further propose a two-step model for NLRP1 activation.
- Qin Gong
- , Kim Robinson
- & Bin Wu
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| Open Access
Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
Inflammasome activation may contribute to type 2 diabetes, but whether targeting inflammasome is beneficial is unclear. Here the authors show that repurposing nucleoside reverse transcriptase inhibitors for inhibiting inflammasome activation is associated with reduced diabetes development in people and improves insulin sensitivity in experimental settings.
- Jayakrishna Ambati
- , Joseph Magagnoli
- & Bradley D. Gelfand
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Indirect regulation of HMGB1 release by gasdermin D
HMGB1 is an inflammatory mediator released by a variety of cell types. Here, the authors show that unlike IL-1β, HMGB1 is released non-specifically following cell lysis.
- Allen Volchuk
- , Anna Ye
- & Neil M. Goldenberg
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Article
| Open Access
Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis
How extracellular calcium can trigger Nlrp3 inflammasome activation has been somewhat controversial and unclear. Here the authors show calciprotein particles are taken up by myeloid cells via calcium-sensing receptor-dependent macropinocytosis in response to high levels of extracellular Ca2+ and this pathway might be critical to inflammatory conditions.
- Elisabeth Jäger
- , Supriya Murthy
- & Ulf Wagner
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Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria
Detection of LPS derived from Gram-negative bacteria by innate immune receptors is a critical step in the host response. Here Santos and colleagues show human GBP1 binds to LPS resulting in non-canonical inflammasome activation.
- José Carlos Santos
- , Dave Boucher
- & Petr Broz
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N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis
In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
- Mausita Karmakar
- , Martin Minns
- & Eric Pearlman
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| Open Access
Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition
NLRP3 activation by Leishmania parasites is critical to the outcome of the disease. Here the authors show that LRV, a virus infecting Leishmania strains associated with more severe human disease, enables the parasite to suppress the inflammasome by activating type 1 interferon through TLR3, which leads to autophagy-mediated NLRP3 degradation.
- Renan V. H. de Carvalho
- , Djalma S. Lima-Junior
- & Dario S. Zamboni
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Article
| Open Access
Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation
The enzyme nicotinate phosphoribosyltransferase (NAPRT) mediates the rate-limiting step in NAD salvage pathway starting from nicotinic acid. Here the authors show that NAPRT can be detected extracellularly, binds to Toll like receptor 4, and activates NF-kB signaling and cytokine production in macrophage via NAD synthesis-independent pathways.
- Antonella Managò
- , Valentina Audrito
- & Silvia Deaglio
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| Open Access
Caspase-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 Access
Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity
The functions of microbial hydrogen peroxide (H2O2) in host-pathogen interactions are unclear. Here, Erttmann and Gekara show that H2O2 released by Streptococcus pneumoniae inhibits inflammasomes, and thereby contributes to the pathogen’s ability to colonize the host.
- Saskia F. Erttmann
- & Nelson O. Gekara
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Article
| Open Access
Alternative splicing regulates stochastic NLRP3 activity
Leucine-rich repeat (LRR) domains are commonly present in immune regulatory proteins. Here the authors show that LRR exonic modularity and alternative splicing of an LRR-containing protein, NLRP3, modulate the ratio of functional/afunctional NLRP3 isoforms to instill a stochastic regulation of NLRP3-mediated inflammation and innate immunity.
- Florian Hoss
- , James L. Mueller
- & Eicke Latz
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Article
| Open Access
Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies
FHR1 is a serum protein implicated in complement regulation. Here the authors show that human FHR1 binds to necrotic cells, triggering inflammasome activation in monocytes in culture, localizes to necrotic tissue and correlates with inflammatory cytokine levels in vasculopathies.
- Sarah Irmscher
- , Silke R. Brix
- & Christine Skerka
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Article
| Open Access
P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis
Systemic sepsis is a potentially life-threatening illness and immunocompromised individuals are especially vulnerable. Here, using a cohort of patients with intra-abdominal origin sepsis, the authors show an important role for the NLRP3 inflammasome in establishing a host response, and NLRP3 dysfunction is a common feature of sepsis mortality.
- Juan José Martínez-García
- , Helios Martínez-Banaclocha
- & Pablo Pelegrin
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Article
| Open Access
Caspase-1 initiates apoptosis in the absence of gasdermin D
In inflammasomes, caspase-1 activation leads to pyroptosis mediated by gasdermin D, but cells lacking gasdermin-D still initiate caspase-dependent cell death. Here, Tsuchiya et al. show that these cells undergo Bid- and caspase-3-dependent apoptosis.
- Kohsuke Tsuchiya
- , Shinsuke Nakajima
- & Takashi Suda
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Article
| Open Access
The lncRNA Neat1 promotes activation of inflammasomes in macrophages
The inflammasomes are important mediators of protective immunity by promoting inflammatory cytokine production and cell death. Here the authors show that a lncRNA, Neat1, is mobilized by inflammasome-activating signals to promote the assembly of several inflammasome complexes and cytokine maturation to regulate inflammation.
- Pengfei Zhang
- , Limian Cao
- & Mian Wu
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Article
| Open Access
NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway
Activation of the NLRP3 inflammasome is associated with various diseases but its activation mechanism is not fully understood. Here, the authors determine the impact of different NLRP3 domains on sensing NLRP3 triggers, inflammasome assembly and regulation of NLRP3 inflammasome activation.
- Iva Hafner-Bratkovič
- , Petra Sušjan
- & Roman Jerala
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Article
| Open Access
Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity
The inflammasome is an essential component of inflammatory processes and the host response to infection. Here the authors show that inflammasome activation modulates MyD88-IRF7 type I IFN signalling and anti-malaria immunity.
- Xiao Yu
- , Yang Du
- & Rong-Fu Wang
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Article
| Open Access
The 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 Access
REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis
REV-ERBα is a nuclear receptor that links the circadian pathways with those of metabolism. Here the authors show REV-ERBα is also involved with linking the circadian system with the inflammatory pathways of an experimental model of colitis through regulation of the NF-κB/NLRP3 axis.
- Shuai Wang
- , Yanke Lin
- & Baojian Wu
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Article
| Open Access
POH1 deubiquitinates pro-interleukin-1β and restricts inflammasome activity
The inflammasomes are important for activating the pro-inflammatory cytokine interleukin-β (IL-1β) for protection against pathogens. Here the authors show that a deubiquitinase, POH1, reduces the conversion of pro-IL-1β into its active form, with in vivo data further implicating a role of POH1 for maintaining immune homeostasis.
- Li Zhang
- , Yun Liu
- & Yongzhong Liu
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Article
| Open Access
Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism
Complement, while serving to remove pathogens in the circulation, is also important for synergizing with inflammasomes to modulate CD4 T cell activation. Here the authors show that CD46, a complement receptor expressed only in humans, is essential for inducing optimal activation and effector functions of human CD8 T cells.
- Giuseppina Arbore
- , Erin E. West
- & Claudia Kemper
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Article
| Open Access
NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease
The inflammasome is normally activated by pathogens to induce tissue inflammation. Here the authors show that, in mouse experimental colitis models, Nlrp1 inflammasome sensor activates IL-18 to reduce beneficial colonic Clostridiales species, thereby decreasing microbial butyrate and its protective effects on colitis.
- Hazel Tye
- , Chien-Hsiung Yu
- & Seth L. Masters
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Article
| Open Access
Sensing of cytosolic LPS through caspy2 pyrin domain mediates noncanonical inflammasome activation in zebrafish
In humans, caspase-5 is an LPS sensor that can induce gasdermin D cleavage and pyroptosis. Here, the authors show that zebrafish caspy2 is a functional homolog as it also senses cytosolic LPS to activate the noncanonical inflammasome and to protect against bacterial infection, but it does so via pyrin death domain interactions.
- Dahai Yang
- , Xin Zheng
- & Qin Liu
Inflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants