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Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis
Although the function of Toll-like receptor 9 (TLR9) in immunity and inflammation is well-established, its role in obesity is less well-studied. In this study, the authors demonstrate that TLR9 deficiency in B cells is associated with obesity in mice and results in altered frequencies of T and B lymphocyte subsets and gut microbiome dysbiosis.
- Pai Wang
- , Xin Yang
- & Li Wen
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Article
| Open Access
Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
The use of oncolytic viruses as a therapy for cancer is limited by mechanisms inhibiting viral replication in the tumor. Here, the authors show that a chemical derivative of itaconate, 4-octyl itaconate, increases oncolytic virus VSVΔ51 efficacy in various cancer models, through decreasing antiviral immunity.
- Naziia Kurmasheva
- , Aida Said
- & David Olagnier
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Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans
Integrin CR3 (CD11b/CD18) is a receptor responsible for recognizing fungal β-glucan. Here, Zhou et al show that the Candida albicans Als family proteins are ligands for the CD11b I domain; an interaction which synergizes with β-glucan to activate CR3.
- Tingting Zhou
- , Norma V. Solis
- & Haoping Liu
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UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors
The RIG-I like receptors sense RNA viruses and initiate antiviral immunity. Here the authors screen 375 definite ubiquitin ligases and propose UBR5 promotes RLR transcription by disengaging the TRIM28-imposed brake on the RLR promoters.
- Duomeng Yang
- , Tingting Geng
- & Penghua Wang
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Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol
Stimulator of interferon genes (STING) is known to translocate from ER to Golgi while orchestrating type I interferon responses to DNA. Here, the authors show single-molecule resolution images of STING clustering at the trans-Golgi network, where it acts as a scaffold to trigger downstream signaling.
- Haruka Kemmoku
- , Kanoko Takahashi
- & Tomohiko Taguchi
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Mucosal TLR5 activation controls healthspan and longevity
Understanding how the immune system’s functionality declines with age is crucial for addressing aging-related health issues. Here, the authors demonstrate that activating TLR5 in the mucosal layer can significantly improve healthspan and longevity, suggesting a novel approach for aging interventions.
- Jae Sung Lim
- , Eun Jae Jeon
- & Kyung A Cho
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Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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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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TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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| Open Access
The E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization
Riplet conjugates K63-Ub chain to RIG-I in order to induce a robust antiviral response, but the mechanism of action remains unclear. Here, the authors show that Riplet recognizes RIG-I regardless of its RNA-bound status and promotes RIG-I signaling independent of RIG-I oligomerization.
- Wenshuai Wang
- , Benjamin Götte
- & Anna Marie Pyle
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C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity
Receptor dimerization can modulate immune responses during various microbial infections. Here, the authors show that C-type lectin receptor-2d (CLEC2D) negatively regulates antifungal immunity through forming homodimers or heterodimers with TLR2.
- Fan Li
- , Hui Wang
- & Xin-Ming Jia
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A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity
The authors identify feeblin, an inhibitory compound of the proinflammatory TLR7/8/9-IRF5 pathway with therapeutic potential, which acts by binding SLC15A4 via an allosteric mechanism mediating degradation of its signaling partner TASL.
- Andras Boeszoermenyi
- , Léa Bernaleau
- & Giulio Superti-Furga
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NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis
The crosstalk between innate immunity and autophagy plays a critical role in cancer. Here, the authors report that an immune receptor NLRP6 potentiates the PI3K/AKT pathway by selective degradation of p85α. The NLRP6-p85α interaction offers a potential therapeutic target for tumor treatment.
- Feng Zhi
- , Bowen Li
- & Jun Cui
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Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen
Fungal pathogens are recognised and phagocytosed by macrophages in the early stages of infection. Here, Onyishi et al. identify a crosstalk between Toll Like Receptor 4 and Macrophage Scavenger Receptor 1 in the regulation of Cryptococcus neoformans uptake.
- Chinaemerem U. Onyishi
- , Guillaume E. Desanti
- & Robin C. May
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WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response
MAVS aggregation initiates innate immune defences and is closely regulated to limit excessive inflammation. Here, Li et al identify and characterise a negative regulator of MAVS signalling and its impact on virus infection.
- Jiaxin Li
- , Rui Zhang
- & Fajian Hou
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High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection
The ambient environmental temperature changes the extent or severity of a virus infection. Here the authors show that influenza and SARS-CoV-2 infection at higher temperatures promotes gut microbiota derived deoxycholic acid signalling which increases host resistance to infection.
- Minami Nagai
- , Miyu Moriyama
- & Takeshi Ichinohe
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PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity
cGAS/STING mediated immunity is linked to the anti-tumor response, but how tumor-intrinsic cGAS signals are countered during tumorigenesis and immune evasion is poorly understood. Here the authors show PRMT1 suppresses the anti-tumor immune response via arginine methylation of cGAS.
- Jing Liu
- , Xia Bu
- & Wenyi Wei
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Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19
Viral infections and exposure to inhaled allergens are linked to asthma onset, exacerbations and progression. Here, the authors used controlled experimental rhinovirus infection in patients with and without asthma, and further assessed in vitro the role of house dust mite allergen combined with rhinovirus and SARS-CoV-2 infection. They discovered that rhinovirus-induced activation of epithelial RIG-I inflammasome supresses antiviral immunity, promotes inflammation during asthma exacerbations and aggravates subsequent infection with SARS-CoV-2, particularly upon house dust mite exposure.
- Urszula Radzikowska
- , Andrzej Eljaszewicz
- & Milena Sokolowska
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A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3
Innate immune evasion is a key aspect of bacterial pathogenesis. Here, Ta et al identify and characterise EhaF, a bacterial autotransporter that functions to inhibit host innate immunity and promote the colonisation and pathogenesis of enterohemorrhagic Escherichia coli.
- Atri Ta
- , Rafael Ricci-Azevedo
- & Sivapriya Kailasan Vanaja
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Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection
Here, de Sá et al. show that Gasdermin-D is transiently activated in Leishmania-infected macrophages and promotes NLRP3 inflammasome activation, but not cell death. Gasdermin-D is cleaved into a noncanonical fragment, indicating that Leishmania subverts Gasdermin-D-mediated host response to establish leishmaniasis.
- Keyla S. G. de Sá
- , Luana A. Amaral
- & Dario S. Zamboni
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APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection
APOBEC’s are a family of cytidine deaminases that induce mutations in viruses to inhibit their replication and maintain cell integrity. Here, Manjunath et al show that APOBEC3B also inhibits viral replication by stimulating the innate immune sensor protein kinase R causing translational shutdown and stress granule formation independently of its cytidine deaminase activity.
- Lavanya Manjunath
- , Sunwoo Oh
- & Rémi Buisson
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Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation
Stimulator of interferon gene (STING) plays critical roles in the host response to infection and in the production of interferon. Here the authors suggests myristic acid is involved in the homeostatic balancing of STING dependent autophagy and the interferon response.
- Mutian Jia
- , Yuanyuan Wang
- & Wei Zhao
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Article
| Open Access
Increased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development
The contribution of transposable elements and endogenous retroviruses to renal fibroinflammation is currently unknown. Here, the authors comprehensively profile the expression of transposable elements and endogenous retroviruses (ERVs) in kidneys of patients and mouse disease models and find expression of ERVs in diseased kidneys activate cytosolic nucleotide sensors contributing to cytokine release and renal fibroinflammation.
- Poonam Dhillon
- , Kelly Ann Mulholland
- & Katalin Susztak
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TLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction
TLR3 activates a potent immune response by binding to dsRNA. Here the authors report cryo-EM analyses to show that TLR3 dimers laterally form a higher multimeric complex along dsRNA, providing the basis for cooperative binding and efficient signal transduction.
- Kentaro Sakaniwa
- , Akiko Fujimura
- & Toshiyuki Shimizu
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| Open Access
RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth
IL-6 and RasGRP1 have been shown to have important functions during inflammation and cancer. Here the authors propose the protein and mRNA of RasGRP1 have opposing functions by promoting IL-6 mediated acute inflammation and inhibiting inflammation-associated cancer through mRNA and protein mechanisms respectively.
- Cong Wang
- , Xue Li
- & Songqing Tang
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Article
| Open Access
TLR3 forms a highly organized cluster when bound to a poly(I:C) RNA ligand
TLR3 plays a crucial role in anti-viral immune response by recognizing RNAs produced during virus infection. Here, the authors determine a high resolution structure of the activated cluster of TLR3. This structure will provide a platform for designing antiviral therapeutics and vaccines.
- Chan Seok Lim
- , Yoon Ha Jang
- & Jie-Oh Lee
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CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses
Modulation of metabolic pathways is linked to regulation of immune cells including macrophages. Here the authors identify a role for CD1d in the metabolic rewiring of macrophages, which alters responsiveness to innate stimuli.
- Phillip M. Brailey
- , Lauren Evans
- & Patricia Barral
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The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS
The activity and stability of the cytosolic DNA sensor cGAS, a key mediator of innate antiviral immunity and autoimmunity, is fine-tuned by post-translational modifications. Here, the authors demonstrate that the ubiquitin E3 ligase ARIH1 catalyzes the mono-ISGylation of cGAS and promotes its oligomerization in response to viral and self DNA.
- Tian-Chen Xiong
- , Ming-Cong Wei
- & Dandan Lin
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| Open Access
Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti
Aedes aegypti can act as a vector for viral pathogens but the mechanism of viral resistance and evolving host-pathogen tolerance are poorly understood. Here the authors structurally characterise a duplicated pair of interacting Toll immunoreceptors and the cytokine ligand Spaetzle1C and show their dose-dependent function and mechanism of activation.
- Yoann Saucereau
- , Thomas H. Wilson
- & Monique Gangloff
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Article
| Open Access
The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation
The anti-viral protein MAVS forms aggregates as part of the antiviral response and promoting type I IFN responses. Here the authors show that protein arginine methyltransferase 9 (PRMT9) methylates MAVS to keep the protein in a non-aggregated state and propose a regulatory mechanism for MAVS.
- Xuemei Bai
- , Chao Sui
- & Chengjiang Gao
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Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling
Guanylate-binding proteins (GBP) have a function in inflammasome formation and pathogen defence. Here the authors show that these GBP proteins are able to kill certain bacteria and promote selective inflammasome activation and that this is mediated by specific GBP protein regions.
- Shouya Feng
- , Daniel Enosi Tuipulotu
- & Si Ming Man
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A degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery
The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.
- Hayden Weng Siong Tan
- , Guang Lu
- & Han-Ming Shen
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| Open Access
Macrophages disseminate pathogen associated molecular patterns through the direct extracellular release of the soluble content of their phagolysosomes
The detection of conserved motifs by pattern recognition receptors is a crucial component of the innate detection of pathogens and danger signals via conserved pattern recognition receptors. Here the authors define a pathway that transfers partially digested material from the phagolysosomal pathway of macrophages to release at the plasma membrane which is associated with enhanced inflammatory potential, by a process they introduce as eructophagy.
- Catherine J. Greene
- , Jenny A. Nguyen
- & Robin M. Yates
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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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| Open Access
Deficiency in coatomer complex I causes aberrant activation of STING signalling
Mutations in the coatomer complex I can result in endoplasmic reticulum stress and inflammatory consequences. Here authors define aberrant activation of the STING immunosensing pathway in a disturbed coatmer complex context and the therapeutic modulation of this axis to counter the associated immunopathology.
- Annemarie Steiner
- , Katja Hrovat-Schaale
- & Seth L. Masters
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| Open Access
Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open Access
Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection
Smallpox is a highly contagious respiratory pathogen associated with a high mortality rate. Here the authors utilize a mouse model of intranasal vaccinia virus infection and show a C7 gene encoded virulence factor attenuates type I IFN release by lung type II alveolar epithelial cells and reduces lung inflammatory monocyte responses.
- Ning Yang
- , Joseph M. Luna
- & Liang Deng
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Article
| Open Access
Human rhinovirus promotes STING trafficking to replication organelles to promote viral replication
Evidence exists that the typically antiviral signaling mediator STING is, counterintuitively, needed for optimal human rhinovirus infection. Here the authors confirm this finding and show how human rhinovirus can reduce stored Ca2+ levels to drive this effect.
- Martha Triantafilou
- , Joshi Ramanjulu
- & Kathy Triantafilou
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Article
| Open Access
Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer
Vaccination with BCG has been shown to induce a pre-priming effect in innate immune cells termed trained immunity. Here the authors re-engineer the BCG vaccine and show augmented immune responses, enhanced induction of trained immunity and improved antitumor efficacy in pre-clinical models of bladder cancer.
- Alok Kumar Singh
- , Monali Praharaj
- & Trinity J. Bivalacqua
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| Open Access
Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7
The interferon response is a critical component of the innate immune response. Here the authors implicate MNDA in the regulation of type I interferon responses to pathogen infection.
- Lili Gu
- , David Casserly
- & Andrew G. Bowie
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Article
| Open Access
Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators
Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.
- Friederike L. Pennemann
- , Assel Mussabekova
- & Andreas Pichlmair
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| Open Access
MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA.
- Qin Yu
- , Alba Herrero del Valle
- & Yorgo Modis
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| Open Access
Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors
Loss of function polymorphisms of phospholipase D3 and D4 are associated with inflammatory diseases and their function is unclear. Here the authors show that PLD3/4 function as RNAses and deletion of these proteins in mice leads to accumulation of ssRNA which exacerbates inflammation through TLR signalling.
- Amanda L. Gavin
- , Deli Huang
- & David Nemazee
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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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| Open Access
Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways
The cytidine deaminase APOBEC3A is a main source of mutagenesis in many types of cancer. Here the authors reveal that transient up-regulation of APOBEC3A and other pro-inflammatory genes can occur due to viral infection and genotoxic stress via multiple pathways.
- Sunwoo Oh
- , Elodie Bournique
- & Rémi Buisson
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Article
| Open Access
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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| Open Access
Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Yi Yang
- , Adam Csakai
- & Hang Yin
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Article
| Open Access
Structural specificities of cell surface β-glucan polysaccharides determine commensal yeast mediated immuno-modulatory activities
Yeast form part of the host microbiome with known impact on host immunity. Here the authors identify and investigate the impact of commensal yeast-derived polysaccharides in modulating host inflammation, and show its potential for inhibiting inflammation in a number of models of inflammatory diseases.
- Changhon Lee
- , Ravi Verma
- & Sin-Hyeog Im
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| Open Access
TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection
Innate immune cells respond to a number of environmental cues including TLR signalling. Here the authors implicate mechanical sensor Piezo1 in the TLR4 mediated host response to bacterial infection and implicate it in the enhancement of macrophage mediated host response.
- Jing Geng
- , Yiran Shi
- & Dawang Zhou
Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans