Common Differences: The Ability of Inflammasomes to Distinguish Between Self and Pathogen Nucleic Acids During Infection

Lupfer, Christopher R.; Rippee-Brooks, Meagan; Anand, Paras

doi:10.1016/bs.ircmb.2018.10.001

Cited by 12 publications

(7 citation statements)

References 126 publications

(189 reference statements)

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“…In our work, DNA from organelles had lower effects than genomic DNA and self-DNA maintained immunogenic properties after methylation with the CpG methyltransferase M.SssI or cleavage of all unmethylated 5'-CCGG-3' motifs. Theoretically, these patterns would be consistent with a model that considers DNA fragmentation as a pre-requisite of immunogenic activity and assumes additive effects of a specific response to unmethylated CpG-motifs and of a non-specific response to dsDNA, as exhibited, e.g., by several mammalian DNA sensors, including cyclic GMP-AMP synthase or by absence in melanoma 2 61,63 (Fig. S7).…”

Section: Discussionsupporting

confidence: 80%

The CpG-dependent plant immune response to self-DNA triggers defence hormone signalling and improves fitness

Durán-Flores

Heil

2023

Preprint

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The accumulation of DNA in the cytoplasm or extracellular space is a signal of danger. Plants respond to this signal with a self/non-self-specific activation of early immune signalling events. Here, we asked whether this specificity translates to fitness-relevant resistance to natural enemies. We treated common bean (Phaseolus vulgaris) plants with self-DNA and with non-self-DNA from other plant species. Self-DNA treatment induced jasmonic acid and decreased feeding by a chewing herbivore (Spodoptera frugiperda), while self- and non-self-DNA induced salicylic acid and reduced the population densities of two fungal pathogens (Botrytis cinerea and Sclerotinia sclerotiorum) and of four bacterial pathogens (Enterobacter sp. strain FCB1, Pseudomonas syringae pv. phaseoli and pv. syringae, and Xanthomonas axonopodis pv. phaseoli). Strikingly, a single self-DNA-treatment increased seed production under field conditions in two seasons ca. 1.5-fold and 3.2-fold, while non-self-DNA had lower or no detectable effects. Stronger responses to self- than non-self-DNA seemingly contradict immunological theory. In mammalian immune cells, toll-like receptor 9 (TLR9) is activated by microbial DNA but also by mitochondrial (mt)DNA that is rich in unmethylated CpG motifs. Using bean suspension cells, we observed stronger immunogenic effects of genomic DNA than chloroplast DNA or mtDNA. Moreover, in vitro methylation or cleavage of CpG motifs reduced – without eliminating – the H2O2-inducing properties of DNA. We conclude that the plant immune response to DNA comprises a self/non-self-specific induction of major defence hormones that can be adaptive under natural enemy pressure and that unmethylated CpG motifs contribute to the immunogenic effects of DNA in plants.

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Section: Discussionsupporting

confidence: 80%

The CpG-dependent plant immune response to self-DNA triggers defence hormone signalling and improves fitness

Durán-Flores

Heil

2023

Preprint

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“…22,[33][34][35][36][37][38] TLRs are evolutionary conserved pattern recognition receptors (PRRs) localized at the cell surface or in endosomal compartments, and act as key mediators of innate immunity. 26,[39][40][41][42][43] As a family, TLRs play a crucial role in ensuring a first line of defense against pathogens, largely based on their ability to respond to conserved microbial structures commonly referred to as microbe-associated molecular patterns (MAMPs) by initiating the secretion of bioactive factors including numerous cytokines. 40,[44][45][46][47] Alongside this pristine antimicrobial function, TLRs also respond to a number of endogenous cues commonly referred to damage-associated molecular patterns (DAMPs), which are critical for the detection of cell stress and death as immunogenic in sterile conditions.…”

Section: Introductionmentioning

confidence: 99%

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Frega

Naour

et al. 2020

OncoImmunology

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Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents.

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“…40 On the other hand, the absent in melanoma 2 (AIM2) inflammasome is activated in response to the cytoplasmic presence of double-stranded DNA (dsDNA). [41][42][43][44][45] Recognition of DNA by AIM2…”

mentioning

confidence: 99%

Lipids, inflammasomes, metabolism, and disease

Anand

2020

Immunological Reviews

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Inflammasomes are multi‐protein complexes that regulate the cleavage of cysteine protease caspase‐1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod‐like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.

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Common Differences: The Ability of Inflammasomes to Distinguish Between Self and Pathogen Nucleic Acids During Infection

Cited by 12 publications

References 126 publications

The CpG-dependent plant immune response to self-DNA triggers defence hormone signalling and improves fitness

The CpG-dependent plant immune response to self-DNA triggers defence hormone signalling and improves fitness

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Lipids, inflammasomes, metabolism, and disease

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