The intricate biophysical puzzle of caspase-1 activation

Makoni, Nyasha J.; Nichols, Michael R.

doi:10.1016/j.abb.2021.108753

Cited by 20 publications

(17 citation statements)

References 114 publications

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“…Using confocal microscopy, the colocalization of the C. difficile flagellin with pro-caspase-1 inside the cell was detected, suggesting an NLRC4 inflammasome assembly. The detection of the activation of pro-caspase-1 by cleavage into subunits p10 and p20 confirmed this inflammasome formation [ 37 ]. As previously described for other flagellins, releasing of mature IL-18 by Caco-2/TC7 cells following internalization of FliC, suggest a role for caspase-1 in the maturation of pro-IL-18.…”

Section: Discussionmentioning

confidence: 85%

Clostridioides difficile Flagellin Activates the Intracellular NLRC4 Inflammasome

Chebly

Marvaud

Safa

et al. 2022

IJMS

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Clostridioides difficile (C. difficile), is a major cause of nosocomial diarrhea and colitis. C. difficile flagellin FliC contributes toxins to gut inflammation by interacting with the immune Toll-like receptor 5 (TLR5) to activate nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways. Flagella of intracellular pathogens can activate the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome pathway. In this study, we assessed whether flagellin of the extracellular bacterium C. difficile internalizes into epithelial cells and activates the NLRC4 inflammasome. Confocal microscopy showed internalization of recombinant green fluorescent protein (GFP)-FliC into intestinal Caco-2/TC7 cell line. Full-length GFP-FliC activates NLRC4 in Caco-2/TC7 cells in contrast to truncated GFP-FliC lacking the C-terminal region recognized by the inflammasome. FliC induced cleavage of pro-caspase-1 into two subunits, p20 and p10 as well as gasdermin D (GSDMD), suggesting the caspase-1 and NLRC4 inflammasome activation. In addition, colocalization of GFP-FliC and pro-caspase-1 was observed, indicating the FliC-dependent NLRC4 inflammasome activation. Overexpression of the inflammasome-related interleukin (interleukin (IL)-1β, IL-18, and IL-33) encoding genes as well as increasing of the IL-18 synthesis was detected after cell stimulation. Inhibition of I-kappa-B kinase alpha (IKK-α) decreased the FliC-dependent inflammasome interleukin gene expression suggesting a role of the NF-κB pathway in regulating inflammasome. Altogether, these results suggest that FliC internalizes into the Caco-2/TC7 cells and activates the intracellular NLRC4 inflammasome thus contributing to the inflammatory process of C. difficile infection.

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Section: Discussionmentioning

confidence: 85%

Clostridioides difficile Flagellin Activates the Intracellular NLRC4 Inflammasome

Chebly

Marvaud

Safa

et al. 2022

IJMS

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“…GA is an acute reaction triggered by MSU, which is one of the prominent clinical features of gout (Ragab et al, 2017). The GA attack is the pathogenic inflammatory response caused by MSU, during which IL-1β, IL-6, IL-10, TNFα, Caspase-1 were all involved in the development of inducing and expanding inflammation (Das et al, 2020;Galozzi et al, 2021;Makoni and Nichols, 2021). NLRP3 and IL-1β have been identified as risk factors for gout, and it has been clinically confirmed that high levels of NLRP3, Caspase-1, IL-1β and IL-6 have been detected in serum and synovial fluid of patients (Son et al, 2013;Cavalcanti et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of the anti-inflammatory effect of Cordyceps militaris extract on acute gouty arthritis

Jiao

Liang²,

Liu³

et al. 2022

Front. Pharmacol.

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Background: Gouty arthritis (GA) is a common inflammatory disease that causes pain due to the deposition of monosodium urate (MSU) crystals into joints and surrounding tissues. Anti-inflammatory drugs have significant clinical anti-inflammatory and analgesic effects, but they have many side effects. Cordyceps militaris is an edible and medicinal fungus, and its extract (CME) has good anti-inflammatory and analgesic effects. This study aimed to investigate the anti-inflammatory effect of CME on GA and its underlying mechanism.Methods: The effect of CME on the expression of related inflammatory factors and histopathological changes in the MSU-induced acute inflammatory gout model in rats was studied by ELISA and HE, and its anti-inflammatory mechanism was analyzed by transcriptome combined with RT-qPCR.Results: CME significantly improved gait scores and joint swelling in GA rats, and reduced MSU-induced inflammatory cell infiltration. CME inhibited MSU-induced inflammatory responses by reducing the levels of pro-inflammatory factors TNF-α, IL-1β, IL-6, and Caspase-1 and increasing the anti-inflammatory factor IL-10. Transcriptome analysis showed that CME significantly altered inflammation-related cytokine pathways, and identified four major genes involved in regulation of inflammation, CCL7, CSF2RB, LIF, and IL-1β. In addition, RT-qPCR was performed to verify these differential genes.Conclusion: CME significantly alleviated the inflammatory progression of GA and ameliorated the onset of GA. The underlying mechanism may be related to triggering the cytokine-cytokine receptor interaction signaling pathway to inhibit the activation of the inflammasome and regulate the immune system. And it regulates the inflammatory response induced by MSU crystals through the genes CCL7, CSF2RB, and IL-1β.

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“…Caspase-1 generally exists in the cytoplasm of cells in the form of zymogen before activation, and activated Caspase-1 can promote the maturation of IL-1β precursor and IL-18 precursor, enabling them to be activated and secreted extracellularly (38). At the same time, Caspases-1 can shear the common substrate of inflammatory Caspases, Gasdermin D (GSDMD), release the active N-terminal, and induce cell membrane perforation, which is the key to cell osmotic dead and mature IL-1β and IL-18 secretion outside the cell (39). The activation of Caspase-1 plays a decisive role in the initiation of programmed pyroptosis (8,9).…”

Section: Mir-223-3p/nlrp3 Signaling Axis Regulated the Progression Of...mentioning

confidence: 99%

“…The activation of Caspase-1 plays a decisive role in the initiation of programmed pyroptosis (8,9). Moreover, NLRP3 inflammasomes belong to the Nod-like receptor protein (NLR) family (13,39). Under the action of stimulation signals, some NLRs can form macromolecular complexes, i.e., inflammasomes.…”

Section: Mir-223-3p/nlrp3 Signaling Axis Regulated the Progression Of...mentioning

confidence: 99%

Effect of miR-223-3p on cell pyroptosis in myelodysplastic syndrome and its mechanism via regulating the expression of NLRP3

Yin¹,

Shen²,

Zhang³

et al. 2022

Cell Mol Biol (Noisy-le-grand)

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This study aimed to investigate the regulatory mechanism of the miR-223-3p/NLRP3 signaling axis in the progression of myelodysplastic syndrome (MDS). For this purpose, SKM-1 cells were transfected and three groups were set up according to different transfection protocols: si-NC group (NLRP3 silencing negative control plasmid), si-NLRP3 group (NLRP3 silencing plasmid), miR-223-3p mimic- NC group (miR-223-3p overexpressing negative control plasmid), miR-223-3p mimic group (miR-223- 3p overexpressing plasmid), miR-223-3p mimic+oe-NLRP3 group and miR-223-3p mimic+oe-NLRP3 group (NLRP3 silencing combined with miR-223-3p overexpressing plasmid). Normal bone marrow cells were used as the control. qRT-PCR was used to detect relative expressions of NLRP3 and miR- 223-3p; and Western blot to detect Ki67, Caspase-1, Gasdermin D, IL-1β, IL-18 and MMP-9 expressions. Cell proliferation detection used CCK-8 assay, cell cycle distribution detection adopted flow cytometry, and cell migration and invasion analyses relied on Transwell assay. Dual-luciferase reporter assay verified the relationship between NLRP3 and miR-223-3p. An animal experiment was finally conducted to confirm the results obtained in cells. Results showed that compared with normal bone marrow cells and K562 cells, there were significantly upregulated NLRP3 expression and upregulated expression of miR-223-3p in SKM-1 cells (all P<0.05). Compared with the si-NC group and mimic-NC group respectively, the si-NLRP3 group and miR-223-3p mimic group showed inhibited proliferation, blocked cells in the G0/M phase, reduced cells in S phase, inhibited cell invasion and migration, decreased expressions of Ki67, Caspase-1, Gasdermin D, IL-1β and IL-18, and MMP-9 (all P<0.05). NLRP3 was the direct target of miR-223-3p. Moreover, compared with the miR-223-3p mimic group, the miR-223-3p mimic+oe-NLRP3 group showed increased expressions of NLRP3, Ki67, Caspase-1, Gasdermin D, IL-1β, IL-18 and MMP-9, promoted proliferation, invasion and migration, and increased cells in S phase (all P<0.05). The animal test revealed that compared with the mimic-NC+ oe- NC group, miR-223-3p mimic+ oe-NC group showed reduced tumor volume and decreased Ki67 expression (both P<0.05); while compared with miR-223-3p mimic+ oe-NC group, miR-223-3p mimic+ oe-NLRP3 group had increased tumor volume and increased Ki67 expression (both P<0.05). It was concluded that overexpression of miR-223-3p can effectively inhibit the expression of NLRP3 and cell pyroptosis in MDS.

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The intricate biophysical puzzle of caspase-1 activation

Cited by 20 publications

References 114 publications

Clostridioides difficile Flagellin Activates the Intracellular NLRC4 Inflammasome

Clostridioides difficile Flagellin Activates the Intracellular NLRC4 Inflammasome

Transcriptomic analysis of the anti-inflammatory effect of Cordyceps militaris extract on acute gouty arthritis

Effect of miR-223-3p on cell pyroptosis in myelodysplastic syndrome and its mechanism via regulating the expression of NLRP3

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