A Membrane Potential- and Calpain-Dependent Reversal of Caspase-1 Inhibition Regulates Canonical NLRP3 Inflammasome

Lü

J Cellular Molecular Medi

et al. 2020

Section: Discussionmentioning

confidence: 84%

Astragaloside IV attenuates inflammatory response mediated by NLRP‐3/calpain‐1 is involved in the development of pulmonary hypertension

Lü

J Cellular Molecular Medi

et al. 2020

“…5 and 6 ). Explanation of this observation is made difficult by the major uncertainties currently surrounding the mechanisms of NLRP3 inflammasome activation ( 23 , 48 ). However, since our results suggest that PI3K class III is needed for NLRP3 inflammasome activation in response to pLL/pLL NP and alum, but not for activation in response to ATP ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of the NLRP3 Inflammasome by Particles from the Echinococcus granulosus Laminated Layer

et al. 2020

The interaction of dendritic cells and macrophages with a variety of rigid non-cellular particles triggers activation of the NLRP3 inflammasome and consequent secretion of IL-1β. Non-cellular particles can also be generated in the context of helminth infection, as these large pathogens often shed their outermost structures during growth and/or moulting. One such structure is the massive, mucin-based, soft and flexible laminated layer (LL), which protects the larval stages of cestodes of the genus Echinococcus. We show that particles from the E. granulosus LL (pLL) trigger NLRP3- and caspase-1-dependent IL-1β in LPS-primed mouse bone marrow-derived dendritic cells (BMDC). This response can be elicited by pLL particles too large for phagocytosis, and nonetheless requires actin dynamics, Syk and PI3K. These three requirements had already been observed in our previous study on the alteration by pLL of BMDC responses to LPS in terms of CD86, CD40, IL-10 and IL-12: however, we now show that these alterations are independent of NLRP3 and caspase-1. In other words, an initial interaction with particles requiring actin dynamics, Syk and PI3K but not phagocytosis elicits both NLRP3-dependent and NLRP3-independent responses. Intraperitoneal injection of pLL induced IL-1β, suggesting that contact with LL materials induces IL-1β in the E. granulosus infection setting. Our results extend NLRP3 inflammasome activation by non-cellular particulate materials both to helminth-derived and to flexible/soft materials.

“…Some reports indicated that cytoplasmic K + concentration significantly influences the activation of NLRP3 inflammasome [24, 25]. The cytoplasmic K + concentration of healthy cells is ~ 140–150 mM, which does not induce NLRP3 activation [26, 27].…”

Section: Discussionmentioning

confidence: 99%

Uric acid regulates NLRP3/IL-1β signaling pathway and further induces vascular endothelial cells injury in early CKD through ROS activation and K+ efflux

Zhou

Ouyang

et al. 2019

BMC Nephrol

Background Chronic kidney disease (CKD) has been considered as a major health problem in the world. Increasing uric acid (UA) could induce vascular endothelial injury, which is closely related to microinflammation, oxidative stress, and disorders of lipids metabolism. However, the specific mechanism that UA induces vascular endothelial cells injury in early CKD remains unknown. Methods Human umbilical vein endothelial cells (HUVECs) were cultured and subjected to different concentrations of UA for different periods. Early CKD rat model with elevated serum UA was established. Western blotting and quantitative real-time PCR (qPCR) were applied for measuring protein and mRNA expression of different cytokines. The animals were sacrificed and blood samples were collected for measurement of creatinine, UA, IL-1β, TNF-α, and ICAM-1. Renal tissues were pathologically examined by periodic acid-Schiff (PAS) or hematoxylin-eosin (HE) staining. Results The expression of IL-1β, ICAM-1, NLRP3 complexes, and activation of NLRP3 inflammasome could be induced by UA, but the changes induced by UA were partially reversed by siRNA NLRP3 or caspase 1 inhibitor. Furthermore, we identified that UA regulated the activation of NLRP3 inflammasome by activating ROS and K + efflux. In vivo results showed that UA caused the vascular endothelial injury by activating NLRP3/IL-1β pathway. While allopurinol could reduce UA level and may have protective effects on cardiovascular system. Conclusions UA could regulate NLRP3/IL-1β signaling pathway through ROS activation and K + efflux and further induce vascular endothelial cells injury in early stages of CKD.