Inflammasomes: Threat-Assessment Organelles of the Innate Immune System

Evavold, Charles L.; Kagan, Jonathan C.

doi:10.1016/j.immuni.2019.08.005

Cited by 131 publications

(137 citation statements)

References 160 publications

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“…Since the initial inflammasome priming stimulus in vivo is more likely to involve multiple PAMPs or DAMPs, we believe that the IRAK1 SMOC-dependent licensing would occur in most physiological scenarios that lead to inflammasome activation, and thus explain the susceptibility of Irak1 -/mice to infections where the IL-1 family cytokines have a critical host protective role. It is also possible that the IRAK1-dependent licensing function contributes to innate immune 'threat assessment' as recently described (Evavold and Kagan, 2019), as IRAK1-SMOCs are more strongly induced by bacteria than purified ligands.…”

Section: Discussionmentioning

confidence: 91%

“…Since in a physiological setting immune cells encounter a cocktail of TLR ligands, there are likely mechanisms to encode a multi-TLR response that are distinct from responses observed from activation with single TLR ligands. Additionally, the host may seek to avoid a fullfledged immune response to very low levels of single TLR ligands that pose no pathogenic threat, while the presence of multiple PRR ligands may exceed a 'threat assessment' threshold and warrant a stronger response (Evavold and Kagan, 2019). This would require some form of coincidence detection to function within the PRR pathways.…”

Section: Introductionmentioning

confidence: 99%

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IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

Vayttaden

Smelkinson²,

Ernst

et al. 2019

Preprint

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The innate immune system signals through various higher order signaling complexes called supramolecular organizing centers (SMOCs), which typically organize components of a single pathway. While innate immune signaling pathways have been largely characterized using single receptor stimuli, responses to pathogens require the coordinated engagement of multiple pathways. Here, we report an IRAK1-containing SMOC formed specifically when multiple receptors are activated, which recruits select components of the TLR, MAPK and inflammasome pathways. This allows for signal flux redistribution from TLRs to inflammasomes and facilitates inflammasome licensing through an MKK7-JNK axis, which is defective in Irak1 -/mice. Furthermore, this defect in Irak1 -/mice manifests in increased susceptibility to inflammasome-sensitive pathogens and diminished IL1 production from inflammasomes after co-TLR priming. Thus, IRAK1SMOCs form a multi-pathway coordinating hub for coincidence detection of microbial signals, which may be employed by innate immune cells as a threat assessment and thresholding mechanism for inflammasome activation.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

Vayttaden

Smelkinson²,

Ernst

et al. 2019

Preprint

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“…However, the exact details of ESAT-6 mediated activation of NLRP3 and caspase-1 remain unclear. Since localization of bacteria and their components in the cytosols of the infected cells is required for the activation of NLRP3 and caspase-1 (39), we speculate that the membrane damaging effects of ESAT-6 may contribute to the activation of NLRP3 and caspase-1 indirectly by aiding in the release of Mtb and its components from the phagolysosome to cytoplasm of infected macrophages (40, 41) and the candidate components with cellular NLRP3 activation remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Jung

Vankayalapati

Samten

2020

Preprint

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TX 75708-3154, phone 29 (903)-877-7665, fax (903) 877-5516, buka.samten@uthct.edu 30 4. Acknowledgment: We thank Dr. Charles A. Dinarello for his thoughtful guidance and 31 discussions.32 5. Brief summary: Mycobacterium tuberculosis stimulated the production of IL-1β by 33 macrophages and in mouse lungs with the activation of NLRP3 and K+ efflux in an ESAT-6 34 dependent manner with the involvement of SAA3. 35 36 37 38 39 40 41 42 43 44 45 46 3 ABSTRACT 47To explore interleukin (IL)-1β production in tuberculosis, we infected mouse bone marrow-derived 48 macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target 49 protein of 6 kDa (ESAT-6) gene deletion (H37Rv:∆3875) or complemented strain (H37Rv:∆3875C) and 50 evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs 51 compared to non-infected BMDMs. In contrast, H37Rv:∆3875 induced significantly less mature IL-1β 52 production despite eliciting comparable levels of pro-IL-1β and IL-8 from BMDMs compared to H37Rv 53 and H37Rv:∆3875C. Blocking either NLRP3 or K + efflux diminished H37Rv-induced IL-1β production 54 by BMDMs. Infection of mice intranasally with H37Rv:∆3875 induced less IL-1β production in the lungs 55 compared with H37Rv.Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1β in 56 mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed 57 genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:∆3875 induced expression of lung 58 SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 59 reduced Mtb-induced IL-1β production by BMDMs. We conclude that the production of SAA3 is required 60 for Mtb stimulated IL-1β production by macrophages in tuberculosis infection. 61 62 63 64 65 66 67 68 69 70Tuberculosis (TB) caused around 1.2 million deaths among HIV-negative people and an additional 71 251,000 deaths among HIV-positive people in 2018 (1), which is mainly due to the lack of a detailed 72 understanding of the molecular mechanisms of interactions between immune cells and the pathogen, 73 Mycobacterium tuberculosis (Mtb). Improved understanding of the host-pathogen interaction will lead to 74 an effective TB vaccine design and an identification of novel drug targets to improve clinical management 75 of drug-resistant TB infections. Macrophages play critical roles in tuberculosis infection as both host cells 76 providing intracellular niche for Mtb infection and growth and effector immune cells fighting against Mtb 77infection by communicating with other immune effector cells by producing different cytokines (2). 78Although IL-1β production by macrophages is pivotal for protection against TB infection (3, 4), several 79 clinical reports showed that IL-1β is also involved in TB pathogenesis. There is significantly increased 80 IL-1β mRNA in the alveolar macrophages and IL-1β protein in bronchoalveolar lavage fluid of TB 81 patients compared with healthy controls (5...

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“…These parameters are all influenced by the antigen physical form, and recent evidence has further proved that their modulation determines the outcome of vaccine immunotherapy (30)(31)(32). Even though the impact of the localization of inflammatory ligands at cellular and organismal levels in activating innate immune cells is being increasingly appreciated (33,34), if the physical form of inflammatory moieties modulates their localization and in turn affects the activation of the innate immune system has been largely overlooked. In this study we report that soluble fungal polysaccharides, while largely devoid of pro-inflammatory activity in vitro and in vivo at the injection site, elicited a unique LN phenotype which was unpredictable based on the current model of Dectin-mediated pro-inflammatory activation but rather explained by their localization to the dLN.…”

Section: Discussionmentioning

confidence: 99%

The physical form of microbial ligands bypasses the need for dendritic cell migration to stimulate adaptive immunity

Borriello

Spreafico

Poli

et al. 2020

Preprint

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A central paradigm of immunology is that the innate immune system first detects infectious agents in peripheral tissues, shortly after a pathogen has breached an epithelial barrier. This detection event is mediated by pattern recognition receptors in phagocytes, which then migrate to draining lymph nodes (dLNs), where information of a microbial encounter is conveyed to T and B lymphocytes to generate adaptive immunity. Through the study of fungal moieties, we present data that challenge this model. We found that soluble fungal polysaccharides are immunosilent in the periphery, but become potent immunogens in the dLN. These ligands completely bypass the need of phagocyte migration and, instead, directly activate an immune response that is most similar to those that typify viral infections. These data establish a class of microbial products that violate a central tenet of the immunological lexicon and illustrate that the physical form (not just the chemical structure) impacts innate and adaptive immunity. Short title (40 characters):The form of PAMPs dictates immunity

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Inflammasomes: Threat-Assessment Organelles of the Innate Immune System

Cited by 131 publications

References 160 publications

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

The physical form of microbial ligands bypasses the need for dendritic cell migration to stimulate adaptive immunity

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