Inflammasome mRNA Expression in Human Monocytes during Early Septic Shock

Fahy, Ruairi J.; Exline, Matthew C.; Gavrilin, Mikhail A.; Bhatt, Nitin; Besecker, Beth; Sarkar, Anasuya; Hollyfield, Jennifer L.; Duncan, Michelle; Nagaraja, Haikady N.; Knatz, Nina L.; Hall, Mark W.; Wewers, Mark D.

doi:10.1164/rccm.200703-418oc

Cited by 79 publications

(75 citation statements)

References 33 publications

(33 reference statements)

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“…In agreement with our findings, Rowe and colleagues and Fahy and colleagues observed delayed apoptosis in neutrophils isolated from LPStreated Casp1 2/2 mice with a transitional inflammatory response (46,47). The authors concluded that caspase-1 was not required for IL-1b activation but likely modulated lung inflammation via IL-18.…”

Section: Discussionsupporting

confidence: 91%

“…In conclusion, inflammasomes are critical regulators of the innate and adaptive immune system that connect cell death and inflammatory pathways (7,9,47). Here, we have found that the inflammasome pathway dependent on caspase-1 is activated in critically ill patients and, furthermore, that increases in circulating IL-18 correlate with disease severity and mortality in the MICU.…”

Section: Discussionmentioning

confidence: 74%

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Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Dolinay

Kim

Howrylak

et al. 2012

Am J Respir Crit Care Med

484

424

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Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. Objectives: We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. Methods: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. Measurements and Main Results: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. Conclusions: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 74%

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Dolinay

Kim

Howrylak

et al. 2012

Am J Respir Crit Care Med

484

424

View full text Add to dashboard Cite

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“…15596-026) and then converted to cDNA. Gene expression was calculated as relative copy numbers, as described previously (30,33). Briefly, C t values of the p62 gene were subtracted from the average Ct of two housekeeping genes (GADPH and CAP1), and the resulting ⌬C t was used in the following equation: RCN ϭ (2 Ϫ⌬Ct ) 100.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, C t values of the p62 gene were subtracted from the average Ct of two housekeeping genes (GADPH and CAP1), and the resulting ⌬C t was used in the following equation: RCN ϭ (2 Ϫ⌬Ct ) 100. The relative copy number of a gene is represented as the number of copies relative to the 100 copies of average housekeeping genes (30,33).…”

Section: Methodsmentioning

confidence: 99%

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

Abdulrahman

Khweek

Akhter

et al. 2013

Journal of Biological Chemistry

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Background: Cystic fibrosis is characterized by defective autophagy and increased Burkholderia cenocepacia infection. Results:The depletion of SQSTM1/p62 from ⌬F508 macrophages improves bacterial clearance via autophagy. Conclusion: p62 expression level determines the fate of B. cepacia infection in ⌬F508 macrophages. Significance: Our study reveals the role of p62 in diseases characterized by protein aggregates that compromise autophagy by consuming essential autophagy molecules.

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“…Quantitative PCR was done in the StepOne Plus machine using SYBR Green PCR mix (Applied Biosystems). The values of target genes were normalized to the values of two housekeeping genes, GAPDH and CAP-1, and expressed as relative copy number, as described previously (52)(53)(54).…”

Section: Real-time Pcrmentioning

confidence: 99%

Activation Of The Pyrin Inflammasome By Intracellular Burkholderia Cenocepacia

Gavrilin¹,

Abdelaziz²,

Mostafa³

et al. 2012

A35. Recent Advances in Phagocyte Biology

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Burkholderia cenocepacia is an opportunistic pathogen that causes chronic infection and induces progressive respiratory inflammation in cystic fibrosis patients. Recognition of bacteria by mononuclear cells generally results in the activation of caspase-1 and processing of IL-1β, a major proinflammatory cytokine. In this study, we report that human pyrin is required to detect intracellular B. cenocepacia leading to IL-1β processing and release. This inflammatory response involves the host adapter molecule ASC and the bacterial type VI secretion system (T6SS). Human monocytes and THP-1 cells stably expressing either small interfering RNA against pyrin or YFP-pyrin and ASC (YFP-ASC) were infected with B. cenocepacia and analyzed for inflammasome activation. B. cenocepacia efficiently activates the inflammasome and IL-1β release in monocytes and THP-1. Suppression of pyrin levels in monocytes and THP-1 cells reduced caspase-1 activation and IL-1β release in response to B. cenocepacia challenge. In contrast, overexpression of pyrin or ASC induced a robust IL-1β response to B. cenocepacia, which correlated with enhanced host cell death. Inflammasome activation was significantly reduced in cells infected with T6SS-defective mutants of B. cenocepacia, suggesting that the inflammatory reaction is likely induced by an as yet uncharacterized effector(s) of the T6SS. Together, we show for the first time, to our knowledge, that in human mononuclear cells infected with B. cenocepacia, pyrin associates with caspase-1 and ASC forming an inflammasome that upregulates mononuclear cell IL-1β processing and release. (24-27), and pyrin (28, 29). Specific inflammasomes assembled in response to the detection of intracellular Salmonella, Legionella, Listeria, Francisella, Shigella, and Pseudomonas have been described (22,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), but the inflammasome platform activated upon Burkholderia infection is unknown.Inflammasome assembly results in caspase-1 activation, which subsequently cleaves biologically inactive pro-IL-1β to its active 17-kDa form (40, 41). IL-1β is the major proinflammatory cytokine associated with the initiation of inflammatory reaction, tissue destruction, and pyroptosis (42). To produce IL-1β, macrophages need two signals: one through TLR ligands that induce gene transcription and another through NLR agonists that activate caspase-1 via the inflammasome complex (43). We have previously reported that B. cenocepacia induces pro-IL-1β synthesis via LPS detection by TLR4 in murine macrophages (44). The subsequent conversion of pro-IL-1β to the mature form depends on caspase-1 activation, as caspase-1 knockout mice did not release IL-1β in response to B. cenocepacia (44). In this study, we show that human pyrin is responsible for intracellular detection of B. cenocepacia to induce IL-1β processing and release. This inflammatory response requires the host adapter molecule ASC and the bacterial type VI secretion system (T6SS). carries a deletion of the icmF gene (45). OD at 600 ...

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Inflammasome mRNA Expression in Human Monocytes during Early Septic Shock

Cited by 79 publications

References 33 publications

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

Activation Of The Pyrin Inflammasome By Intracellular Burkholderia Cenocepacia

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