Macrophages, rather than DCs, are responsible for inflammasome activity in the GM-CSF BMDC model

Erlich, Ziv; Shlomovitz, Inbar; Edry-Botzer, Liat; Cohen, Hadar; Frank, Daniel; Wang, Hanqing; Lew, Andrew M.; Lawlor, Kate E.; Zhan, Yifan; Vince, James E.; Gerlic, Motti

doi:10.1038/s41590-019-0313-5

Cited by 89 publications

(95 citation statements)

References 37 publications

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“…These cell types show different responses to inflammasome stimuli; for example, neutrophils are less susceptible to pyroptosis compared to macrophages . In mice, it was shown that differentiation protocols used to generate dendritic cells and macrophages determine the response to inflammasome inducers, further demonstrating how context affects inflammasome activation and the difficulty to extrapolate the nature and contribution of signal 1 from in vitro studies to physiological or pathological conditions …”

Section: Cell Types Competent For Inflammasome Activationmentioning

confidence: 99%

“…47 In mice, it was shown that differentiation protocols used to generate dendritic cells and macrophages determine the response to inflammasome inducers, further demonstrating how context affects inflammasome activation and the difficulty to extrapolate the nature and contribution of signal 1 from in vitro studies to physiological or pathological conditions. 55 While poorly understood, inflammasome activation can also occur in non-phagocytic cells, such as T cells, endothelial cells, and epithelial cells. For example, in immune and non-immune cells of the gut, inflammasome activation such as the NLRP6 and NLRC4 inflammasomes contributes to the maintenance of gut microbiota and gut-brain homeostasis.…”

Section: Cell T Ype S Compe Tent For Infl Amma Some Ac Tivationmentioning

confidence: 99%

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Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

117

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Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

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Section: Cell Types Competent For Inflammasome Activationmentioning

confidence: 99%

Section: Cell T Ype S Compe Tent For Infl Amma Some Ac Tivationmentioning

confidence: 99%

Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

117

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“…Although the mechanism leading to the second, slower step remains to be elucidated, we showed that the first, rapid step is mediated by VPRH-dependent activation of the inflammasome. It is plausible that the second, slower step of cell death observed in BMDMs is mediated by the same mechanism that induced VPRH-dependent cell death in HeLa and RAW 264.7 cells that lack a 19 functional inflammasome. Using a combination of genetic and chemical approaches, we identified the NLRP3 inflammasome as the specific pathway responsible for the VPRH-induced rapid cell death in BMDMs.…”

Section: Discussionmentioning

confidence: 99%

“…In this work, we sought to determine the effect of VPRH on primary immune cells. To this end, we repeated our original experiments, but with the addition of BMDMs, a known model for immune response cells, and a first-line defense against foreign invaders [19]. Importantly, BMDMs are also known to contain a full set of cell death mechanisms, including pyroptosis and necroptosis, as opposed to HeLa and RAW 264.7 cells [9,19].…”

Section: Accelerated Vprh-induced Cell Death In Primary Macrophagesmentioning

confidence: 99%

“…To this end, we repeated our original experiments, but with the addition of BMDMs, a known model for immune response cells, and a first-line defense against foreign invaders [19]. Importantly, BMDMs are also known to contain a full set of cell death mechanisms, including pyroptosis and necroptosis, as opposed to HeLa and RAW 264.7 cells [9,19]. As shown in Figure 1A HeLa, RAW 264.7, or BMDM cells were seeded into 96-well plates in triplicate, and were infected with wild-type (WT) V. proteolyticus or a mutant in which we deleted vprh (Δvprh), at the multiplicity of infection (MOI) 20.…”

Section: Accelerated Vprh-induced Cell Death In Primary Macrophagesmentioning

confidence: 99%

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Vibriopore-forming leukocidin activates pyroptotic cell death via the NLRP3 inflammasome

Baram

Cohen

Edry-Botzer

et al. 2019

Preprint

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Cell death mechanisms are central to combat infectious microbes and to drive pathological inflammation. One such mechanism, the inflammasome, controls infection through either activation of caspase-1 and the subsequent secretion of the mature pro-inflammatory cytokine, interleukin 1b (IL-1b), or by stopping the dissemination of intracellular pathogens by inducing pyroptotic cell death in infected cells. Hemolysins, which are pore-forming toxins (PFTs), target the host cell plasma membrane by producing pores with different diameters. These pores alter the permeability of the target membrane, often leading to cell death. We previously discovered a functional and potent pore-forming, leukocidin domain-containing hemolysin produced by the Gram-negative marine bacterium Vibrio proteolyticus (V. proteolyticus), termed VPRH. Although leukocidin domains are found in other known PFTs, VPRH constitutes a distinct, understudied class within the leukocidin superfamily. Since PTFs of other pathogens were shown to induce cell death by activating the inflammasome pathway, we hypothesized that VPRH-induced cell death is mediated by direct activation of the inflammasome in mammalian immune host cells.Indeed, we found that VPRH induced a two-step cell death in primary macrophages.The first, a rapid step, was mediated by activating the NLRP3 inflammasome, leading to caspase-1 activation and GSDMD cleavage that resulted in IL-1β secretion and pyroptotic cell death. The second step was independent of the inflammasome; however, its mechanism remains unknown. This study sets the foundation for better understanding the immunological consequences of inflammasome activation by a new leukocidin class of toxins.

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Soluble and Microparticle‐Based Delivery of TLR4 and TLR9 Agonists Differentially Modulate 3D Chemotaxis of Bone Marrow‐Derived Dendritic Cells

Atalis

Dixon

Roy

2021

Adv Healthcare Materials

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Vaccines are commonly administered subcutaneously or intramuscularly, and local immune cells, notably dendritic cells (DCs), play a significant role in transporting vaccine antigens and adjuvants to draining lymph nodes. Here, it is compared how soluble and biomaterial‐mediated delivery of Toll‐like receptor (TLR)‐targeted adjuvants, monophosphoryl lipid A (MPLA, TLR4 ligand) and 5'‐C‐phosphate‐G‐3' DNA (CpG DNA, TLR9 ligand), modulate 3D chemotaxis of bone marrow‐derived dendritic cells (BMDCs) toward lymphatic chemokine gradients. Within microfluidic devices containing 3D collagen‐based matrices to mimic tissue conditions, soluble MPLA increases BMDC chemotaxis toward gradients of CCL19 and CCL21, while soluble CpG has no effect. Delivering CpG on poly(lactic‐co‐glycolic) acid microparticles (MPs) enhances BMDC chemotaxis compared to MPLA‐encapsulated MPs, and when co‐delivered, MPLA and CpG do not synergistically enhance BMDC migration. It is concluded that supplementing granulocyte‐macrophage colony stimulating factor‐derived BMDC culture with interleukin‐4 is necessary to induce CCR7 expression and chemotaxis of BMDCs. Different cell subsets in BMDC culture upregulate CCR7 in response to soluble versus biomaterial‐loaded MPLA and CpG, and CCR7 expression does not consistently correlate with functional migration. The results show both adjuvant type and delivery method influence chemotaxis of DCs, and these findings uncover new directions for the rational design of vaccine formulations.

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Macrophages, rather than DCs, are responsible for inflammasome activity in the GM-CSF BMDC model

Cited by 89 publications

References 37 publications

Inflammasomes contributing to inflammation in arthritis

Inflammasomes contributing to inflammation in arthritis

Vibriopore-forming leukocidin activates pyroptotic cell death via the NLRP3 inflammasome

Soluble and Microparticle‐Based Delivery of TLR4 and TLR9 Agonists Differentially Modulate 3D Chemotaxis of Bone Marrow‐Derived Dendritic Cells

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