The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

Burke, Ryan M.; Dale, Bethany L.; Dholakia, Shamik

doi:10.3390/ijms221910721

Cited by 13 publications

(10 citation statements)

References 122 publications

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“…Cell apoptosis-induced activation of inflammasomes is associated with cardiac allograft rejection ( 67 ). Caspase-1 activation is triggered by the assembly of inflammasome complexes, particularly Nlrp3, which function as sensors for ‘danger’ molecules or non-self signals, such as donor-derived cell-free DNA, in the context of organ transplantation ( 55 , 68 , 69 ). Caspase-1 leads to pyroptosis, a process of programmed cell death that includes cell swelling, membrane rupture, and release of cytosolic contents ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection

Wu,

Liang,

Zhu

et al. 2023

Front. Immunol.

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AimsUnderstanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets.MethodsA heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors.ResultsA total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function.ConclusionThe single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection.

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Section: Discussionmentioning

confidence: 99%

Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection

Wu,

Liang,

Zhu

et al. 2023

Front. Immunol.

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“…We tested this hypothesis by examining the expression of related factors after NLRP3 inflammasome activation. NLRP3 inflammasomes regulate caspase-1 activation and promote the maturation and secretion of IL-1β during the natural immune defense ( Burke et al, 2021 ); they also regulate caspase-1-dependent programmed apoptosis and induce cell death under inflammatory and stressful pathological conditions ( Swanson et al, 2019 ). As shown in Figure 8 , we concluded that FA protects against I/R injury by inhibiting NLRP3 inflammasomes in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Farrerol Alleviates Myocardial Ischemia/Reperfusion Injury by Targeting Macrophages and NLRP3

2022

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Myocardial ischemia/reperfusion (I/R) injury is associated with high mortality and morbidity, however, it has no curative treatment. Farrerol (FA), an active compound extracted from rhododendron, has antibacterial, anti-inflammatory, and antioxidant activities, but its effect and mechanism of FA in I/R injury remain unclear. Here, we found that FA alleviated myocardial I/R in vivo, and decreased the secretion of myocardial injury factors (CK-MB, LDH, troponin-1, and NT-proBNP) while inhibiting the release of inflammatory factors (IL-1β, IL-6, and TNF-α). FA could also alleviate excessive oxidative stress by elevating the level of antioxidant enzymes and reducing oxidation products; and decreased reduced the expression of apoptosis-associated proteins (cleaved caspase-3, Bax, and Bcl-2). However, inhibiting the autophagic pathway or knocking out the Nrf2 gene did not eliminate the myocardial protective effect of FA, but interestingly, macrophage clearance and Nlrp3 deficiency effectively blocked the myocardial protective effect of FA. In addition, FA suppressed NLRP3 inflammasome activation by interfering with NLRP3 and NEK7. In conclusion, these results support drug-targeted macrophage therapy for myocardial I/R and indicate that FA may be used as an immunomodulator in clinical therapy for myocardial I/R.

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“…Abnormally increased NLR in peripheral blood is a core indicator and mediator of systemic inflammation of any origin, including in COVID-19 [ 27 , 28 , 29 , 30 , 31 ]. Neutrophils, although essential for defense against infections, also participate in tissue destruction when their activity becomes overly exuberant, as occurs in human pathological inflammatory states for which dapsone is used such as bullous pemphigoid, Behcet’s disease, dermatitis herpetiformis, etc.…”

Section: Rationalementioning

confidence: 99%

Dapsone Lowers Neutrophil to Lymphocyte Ratio and Mortality in COVID-19 Patients Admitted to the ICU

Kanwar¹,

Khattak²,

Kast³

2022

IJMS

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Some physicians use dapsone as part of the standard treatment of severe COVID-19 patients entering the ICU, though some do not. To obtain an indication of whether dapsone is helping or not, we undertook a retrospective chart review of 29 consecutive ICU COVID-19 patients receiving dapsone and 30 not receiving dapsone. As we previously reported, of those given dapsone, 9/29 (30%) died, while of those not given dapsone, 18/30 (60%) died. We looked back on that data set to determine if there might be basic laboratory findings in these patients that might give an indication of a mechanism by which dapsone was acting. We found that the neutrophil-to-lymphocyte ratio decreased in 48% of those given dapsone and in 30% of those not given dapsone. We concluded that dapsone might be lowering that ratio. We then reviewed collected data on neutrophil related inflammation pathways on which dapsone might act as presented here. As this was not a controlled study, many variables prevent drawing any conclusions from this work; a formal, randomized controlled study of dapsone in severe COVID-19 is warranted.

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The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

Cited by 13 publications

References 122 publications

Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection

Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection

Farrerol Alleviates Myocardial Ischemia/Reperfusion Injury by Targeting Macrophages and NLRP3

Dapsone Lowers Neutrophil to Lymphocyte Ratio and Mortality in COVID-19 Patients Admitted to the ICU

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