Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators

Liu, Dongling; Zeng, Xiang; Xiao, Li; Cui, Chaochu; Hou, Ruanling; Guo, Zhikun; Mehta, Jawahar L.; Wang, Xianwei

doi:10.1016/j.bcp.2020.113863

Cited by 68 publications

(50 citation statements)

References 190 publications

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“…These activating signals are classified into (i) exogenous pathogen-associated molecular pattern molecules (PAMPs), which are microbial, fungal, viral, and parasitic products released during infection and, what is more important for the topic of this review, also by (ii) endogenous danger-associated molecular pattern molecules (DAMPs), also known as alarmines that are released during nonpathogen-related "sterile inflammation" [35]. DAMPs, which are secreted after cell activation or damage, include (i) extracellular adenosine triphosphate (eATP), which is a principal mediator of purinergic signaling, (ii) reactive oxygen species (ROS), (iii) the nuclear protein high mobility group protein B1 (HMGB1), (iv) a multigenic family of calcium-modulated proteins, including S1009a and S1008a, (v) uric acid crystals, and (vi) extracellular DNA and RNA fragments [4,[36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

et al. 2020

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Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.

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Section: Introductionmentioning

confidence: 99%

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

et al. 2020

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“…Caspase-1 is a core component of the inflammasome complexes [16] which regulate activation, production, and secretion of the pro-inflammatory cytokines IL-1β and IL-18 [17]. Importantly, recent studies suggest that inflammasomes are involved in many neurodegenerative and cerebrovascular diseases [18,19].…”

Section: Introductionmentioning

confidence: 99%

Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair

Israelov

Ravid

Atrakchi

et al. 2020

J Neuroinflammation

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Background Excessive inflammation might activate and injure the blood-brain barrier (BBB), a common feature of many central nervous system (CNS) disorders. We previously developed an in vitro BBB injury model in which the organophosphate paraoxon (PX) affects the BBB endothelium by attenuating junctional protein expression leading to weakened barrier integrity. The objective of this study was to investigate the inflammatory cellular response at the BBB to elucidate critical pathways that might lead to effective treatment in CNS pathologies in which the BBB is compromised. We hypothesized that caspase-1, a core component of the inflammasome complex, might have important role in BBB function since accumulating evidence indicates its involvement in brain inflammation and pathophysiology. Methods An in vitro human BBB model was employed to investigate BBB functions related to inflammation, primarily adhesion and transmigration of peripheral blood mononuclear cells (PBMCs). Caspase-1 pathway was studied by measurements of its activation state and its role in PBMCs adhesion, transmigration, and BBB permeability were investigated using the specific caspase-1 inhibitor, VX-765. Expression level of adhesion and junctional molecules and the secretion of pro-inflammatory cytokines were measured in vitro and in vivo at the BBB endothelium after exposure to PX. The potential repair effect of blocking caspase-1 and downstream molecules was evaluated by immunocytochemistry, ELISA, and Nanostring technology. Results PX affected the BBB in vitro by elevating the expression of the adhesion molecules E-selectin and ICAM-1 leading to increased adhesion of PBMCs to endothelial monolayer, followed by elevated transendothelial-migration which was ICAM-1 and LFA-1 dependent. Blocking caspase-8 and 9 rescued the viability of the endothelial cells but not the elevated transmigration of PBMCs. Inhibition of caspase-1, on the other hand, robustly restored all of barrier insults tested including PBMCs adhesion and transmigration, permeability, and VE-cadherin protein levels. The in vitro inflammatory response induced by PX and the role of caspase-1 in BBB injury were corroborated in vivo in isolated blood vessels from hippocampi of mice exposed to PX and treated with VX-765. Conclusions These results shed light on the important role of caspase-1 in BBB insult in general and specifically in the inflamed endothelium, and suggest therapeutic potential for various CNS disorders, by targeting caspase-1 in the injured BBB.

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“…Previously, using Syk knockout cells, it was shown that Syk is a positive mediator of NLRP3 inflammasome activation. 69 On the contrary, it is known that in BMDM the release of IL-1β is induced by a two-step regulation, 70,71 and our results showed that BAY significantly reduced the protein levels of NLRP3, ASC, caspase-1 in BMDM and AKI, suggesting that BAY exhibited an inhibitory effect on IL-1β, which may be achieved through blocking the mRNA induction of mature IL-1β by Mincle/Syk/NF-κB and inhibiting the cleavage of pro-IL-1β mediated by NLRP3 inflammasomes. Interestingly, overexpression of Mincle by TDB activated Mincle/Syk/ NF-κB feedback circuit, increased BAY inhibited ROS production and inflammasome activation, suggesting that inhibition of inflammation by BAY is associated with blocking Mincle/Syk/NF-κB feedback circuit and ROS-dependent activation of NLRP3 inflammasome.…”

Section: Discussionmentioning

confidence: 99%

BAY61‐3606 protects kidney from acute ischemia/reperfusion injury through inhibiting spleen tyrosine kinase and suppressing inflammatory macrophage response

Tan

Liu

et al. 2020

The FASEB Journal

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Acute kidney injury (AKI) is a highly prevalent clinical syndrome with high mortality and morbidity. Previous studies indicated that inflammation promotes tubular damage and plays a key role in AKI progress. Spleen tyrosine kinase (Syk) has been linked to macrophage-related inflammation in AKI. Up to date, however, no Syk-targeted therapy for AKI has been reported. In this study, we employed both cell model of LPS-induced bone marrow-derived macrophage (BMDM) and mouse model of ischemia/reperfusion injury (IRI)-induced AKI to evaluate the effects of a Syk inhibitor, BAY61-3606 (BAY), on macrophage inflammation in vitro and protection of kidney from AKI in vivo. The expression and secretion of inflammatory cytokines, both in vitro and in vivo, were significantly inhibited even back to normal levels by BAY. The upregulated serum creatinine and blood urea nitrogen levels in the AKI mice were significantly reduced after administration of BAY, implicating a protective effect of BAY on kidneys against IRI. Further analyses from Western blot, immunofluorescence staining and flow cytometry revealed that BAY inhibited the Mincle/Syk/NF-κB signaling circuit and reduced the inflammatory response. BAY also inhibited the reactive oxygen species (ROS), which further decreased the Talents, Grant/Award Number: Lan HuiYao Team formation of inflammasome and suppressed the mature of IL-1β and IL-18. Notably, these inhibitory effects of BAY on inflammation and inflammasome in BMDM were significantly reversed by Mincle ligand, trehalose-6,6-dibehenate. In summary, these findings provided compelling evidence that BAY may be an efficient inhibitor of the Mincle/Syk/NF-κB signaling circuit and ROS-induced inflammasome, which may help to develop Syk-inhibitors as novel therapeutic agents for AKI.

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Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators

Cited by 68 publications

References 190 publications

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair

BAY61‐3606 protects kidney from acute ischemia/reperfusion injury through inhibiting spleen tyrosine kinase and suppressing inflammatory macrophage response

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