Dataset Information

NLRP3 Inflammasome Activation Regulates Aged RBC Clearance.

ABSTRACT: The NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome is triggered by various stimuli. Whether the NLRP3 inflammasome is activated during the monocyte clearing of aged or damaged erythrocytes is unknown. This work aimed to determine whether the NLRP3 inflammasome is activated during the THP-1 cell engulfing of aged erythrocytes. In the study, THP-1 cells were treated with PMA and then coincubated with untreated red blood cells (RBCs), 42 °C-treated RBCs, immunoglobulin G (IgG) anti-D-sensitized RBCs, Rhnull/Rhmod RBC sample, hemoglobin, and RBC ghost. The activation of the NLRP3 inflammasome and production of some proinflammatory cytokines were determined using immunoblotting, cytometric bead array, and digital PCR. An NLRP3 inflammasome inhibitor was also used to evaluate the alteration of the NLRP3 activation and RBC clearance rate. The untreated RBCs, 42 °C-incubated RBCs, IgG-opsonized RBCs, Rhnull/Rhmod RBCs, RBC ghosts, and hemoglobin induced the THP-1-cell-mediated activation of the NLRP3 inflammasome and the production of inflammatory cytokines. The RBC clearance rate exhibited a positive correlation with the expression of proinflammatory cytokines. The NLRP3 inflammasome inhibitor reduced the NLRP3 activation and RBC phagocytosis rate. The NLRP3 inflammasome was activated during the clearance of the aged erythrocytes through unopsonized and opsonized pathways. However, the mechanism of such phenomenon needs to be further elucidated. Such mechanism may provide new insight into the assessment of the safety of transfusing long-storage RBC based on cytokine levels.

SUBMITTER: Qin L

PROVIDER: S-EPMC6061012 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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NLRP3 Inflammasome Activation Regulates Aged RBC Clearance.

Qin Li L Fengyong Zhao Z Jiamin Zhang Z Qixiu Yang Y Geming Lu L Rongwei Xia X Ziyan Zhu Z

Inflammation 20180801 4

The NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome is triggered by various stimuli. Whether the NLRP3 inflammasome is activated during the monocyte clearing of aged or damaged erythrocytes is unknown. This work aimed to determine whether the NLRP3 inflammasome is activated during the THP-1 cell engulfing of aged erythrocytes. In the study, THP-1 cells were treated with PMA and then coincubated with untreated red blood cells (RBCs), 42 °C-treated RBCs, immunoglobulin G (IgG) an ...[more]

PMID: 29680907

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Project description:BackgroundPersistent inflammation dysregulation and cognitive decline have been associated with several trauma- and stress-related disorders such as posttraumatic stress disorder (PTSD) and anxiety disorder. Despite the abundant discoveries of neuroinflammation in such disorders, the underlying mechanisms still remain unclear.MethodWild-type and Nlrp3-/- mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Three hours after the electric foot shocks, activation of the NLRP3 inflammasome was investigated through immunoblotting and ELISA. Microglia were isolated and analyzed by quantitative real-time PCR. Hippocampal tissues were collected 3 h and 72 h after the electric foot shocks and subjected to RNA sequencing. MCC950 was administrated to mice via intraperitoneal (i.p.) injection. Interleukin-1 receptor antagonist (IL-ra) and interleukin-1β (IL-1β) were delivered via intracerebroventricular (i.c.v.) infusion. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test.ResultsWe demonstrated that, in the contextual fear memory paradigm, the NLRP3 inflammasome was activated 3 h after electric foot shocks. We also found an upregulation in toll-like receptor and RIG-I-like receptor signaling, and a decrease in postsynaptic density (PSD) related proteins, such as PSD95 and Shank proteins, in the hippocampus 72 h after the electric foot shocks, indicating an association between neuroinflammation and PSD protein loss after stress encounter. Meanwhile, Nlrp3 knockout could significantly prevent both neuroinflammation and loss of PSD-related proteins, suggesting a possible protective role of NLRP3 deletion during this process. For further studies, we demonstrated that both genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome remarkably enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior caused by electric foot shocks. Moreover, cytokine IL-1β administration inhibited the extinction of contextual fear memory. Meanwhile, IL-1ra significantly enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior.ConclusionTaken together, our data revealed the pivotal role of NLRP3 inflammasome activation in the regulation of fear memory and the development of PTSD and anxiety disorder, providing a novel target for the clinical treatment of such disorders.

Dataset Information

NLRP3 Inflammasome Activation Regulates Aged RBC Clearance.

Publications

NLRP3 Inflammasome Activation Regulates Aged RBC Clearance.

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