NLRP3/ASC-mediated alveolar macrophage pyroptosis enhances HMGB1 secretion in acute lung injury induced by cardiopulmonary bypass

Abstract

Our previous study showed that high levels of HMGB1 existed in rats following cardiopulmonary bypass (CPB)-induced acute lung injury (ALI) and neutralization of high-mobility group box 1(HMGB1) reduced CPB-induced ALI. However, the mechanism by which CPB increases HMGB1 secretion is unclear. Recent studies have shown that inflammasome-mediated cell pyroptosis promotes HMGB1 secretion. This study aimed to investigate the relationship between inflammasome-mediated pyroptosis and HMGB1 in CPB-related ALI. We employed oxygen-glucose deprivation (OGD)-induced alveolar macrophage (AM) NR8383 pyroptosis to measure HMGB1 secretion. We found that OGD significantly increased the levels of caspase-1 cleaved p10, IL-1β and ASC expression, caspase-1 activity and the frequency of pyroptotic AM, and promoted the cytoplasm transportation and secretion of HMGB1, which were significantly mitigated by ASC silencing or pre-treatment with glyburide (a Nlrp3 inhibitor) in AM. CPB also increased the expression levels of Nlrp3, ASC, caspase-1 P10, and IL-1β, and the percentages of AM pyroptosis in the lungs of experimental rats accompanied by increased levels of serum and bronchoalveolar lavage fluid (BALF) HMGB1. Treatment with glyburide significantly mitigated the CPB-increased ASC, caspase-1 p10 and IL-1β expression, and the percentages of AM pyroptosis in the lungs, as well as the levels of HMGB1 in serum and BALF in rats. Therefore, our data indicated that the Nlrp3/ASC-mediated AM pyroptosis increased HMGB1 secretion in ALI induced by CPB. These findings may provide a therapeutic strategy to reduce lung injury and inflammatory responses during CPB.

Calreticulin Blockade Attenuates Murine Acute Lung Injury by Inducing Polarization of M2 Subtype Macrophages

“…Further analysis by ELISA assay showed that MNs predepletion in conjunction with administration of aCALR additively suppressed the expression of pro-inflammatory cytokines, including TNF-alpha, IL-6 and IL-1beta in lung tissues ( Figure 6A) and BAL (Figure 6B). Cell pyroptosis is characterized with activation of NLRP3 inflammasome and release of both IL-1beta and IL-18 (39)(40)(41). Consistent with the results above, we observed moderately lower expression of IL-18 in the lung (Figure 6C, right panel) of aCALR-treated mice with or without MNs pre-depletion, indicating the suppressive effects of aCALR on macrophage pyroptosis independent of MNs.…”

“…NLRP3 is a key component of NLRP3 inflammasome during cell pyroptosis, contributing to the uncontrolled lung inflammation in ARDS/ALI (39,41). However, it remains unknown whether macrophage pyroptosis is involved in the immune suppressive effects of aCALR.…”

“…IL-1beta and IL-18 are exclusively expressed in pyroptotic cells. NLRP3 is key protein component of NLRP3 inflammasome during cell pyroptosis (39,44). To further define the role of aCALR on macrophage pyroptosis, we analyzed NLRP3 expression in the treated BMDMs.…”

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells

“…Chang and colleagues demonstrated that LPC induces cytotoxicity/apoptosis and IL-8 production in human endothelial cells via mechanisms dependent on ROS, ATM/Chk2, ATR/Chk2, and PI3K/Akt signaling (67). Pyroptosis is a form of proinflammatory cell death and (68) can be mediated by inflammasome-dependent caspase-1 activation (69) or caspase-11 (70), which is responsible for the cleavage and/or maturation of gasdermin D (GSDMD) and membrane pore formation (71), IL-1β (72), IL-18 (73), HMGB1 (74), and LDH release (75). Pyroptosis has been shown to play important roles in cardiovascular diseases, such as atherosclerosis (76).…”

A focused review on materials and generations of coronary stents

“…A cardiopulmonary bypass machine is used in this surgery to circulate oxygenated blood through body during the operation. 32 For removing carbon dioxide used a machine that is pumped blood out of heat and then the machine is filled with oxygen. The oxygenated blood is pumped back into body without going through the heart and lungs.…”