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NF-?B-to-AP-1 switch: a mechanism regulating transition from endothelial barrier injury to repair in endotoxemic mice.

ABSTRACT: Endothelial barrier disruption is a hallmark of multiple organ injury (MOI). However, mechanisms governing the restoration of endothelial barrier function are poorly understood. Here, we uncovered an NF-?B-to-AP-1 switch that regulates the transition from barrier injury to repair following endotoxemic MOI. Endothelial NF-?B mediates barrier repair by inhibiting endothelial cell (EC) apoptosis. Blockade of endothelial NF-?B pathway activated the activator protein (AP)-1 pathway (NF-?B-to-AP-1 switch), which compensated for the anti-apoptotic and barrier-repair functions of NF-?B. The NF-?B-to-AP-1 switch occurred at 24 hours (injury to repair transition phase), but not at 48 hours (repair phase) post-LPS, and required an inflammatory signal within the endothelium. In the absence of an inflammatory signal, the NF-?B-to-AP-1 switch failed, resulting in enhanced EC apoptosis, augmented endothelial permeability, and impeded transition from barrier injury to recovery. The NF-?B-to-AP-1 switch is a protective mechanism to ensure timely transition from endothelial barrier injury to repair, accelerating barrier restoration following MOI.

SUBMITTER: Liu G

PROVIDER: S-EPMC4078303 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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NF-κB-to-AP-1 switch: a mechanism regulating transition from endothelial barrier injury to repair in endotoxemic mice.

Liu Gang G Ye Xiaobing X Miller Edmund J EJ Liu Shu Fang SF

Scientific reports 20140702

Endothelial barrier disruption is a hallmark of multiple organ injury (MOI). However, mechanisms governing the restoration of endothelial barrier function are poorly understood. Here, we uncovered an NF-κB-to-AP-1 switch that regulates the transition from barrier injury to repair following endotoxemic MOI. Endothelial NF-κB mediates barrier repair by inhibiting endothelial cell (EC) apoptosis. Blockade of endothelial NF-κB pathway activated the activator protein (AP)-1 pathway (NF-κB-to-AP-1 swi ...[more]

PMID: 24986487

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Project description:BackgroundSpecificity protein (Sp) 1 mediates the transcription of a large number of constitutive genes encoding physiological mediators. NF-κB mediates the expression of hundreds of inducible genes encoding pathological mediators. Crosstalk between Sp1 and NF-κB pathways could be pathophysiologically significant, but has not been studied. This study examined the crosstalk between the two pathways and defined the role of NF-κB signaling in LPS-induced down-regulation of Sp1 activity.Methods and main findingsChallenge of wild type mice with samonelia enteritidis LPS (10 mg/kg, i.p.) down-regulated Sp1 binding activity in lungs in a time-dependent manner, which was concomitantly associated with an increased NF-κB activity. LPS down-regulates Sp1 activity by inducing an LPS inducible Sp1-degrading enzyme (LISPDE) activity, which selectively degrades Sp1 protein, resulting in Sp1 down-regulation. Blockade of NF-κB activation in mice deficient in NF-κB p50 gene (NF-κB-KO) suppressed LISPDE activity, prevented Sp1 protein degradation, and reversed the down-regulation of Sp1 DNA binding activity and eNOS expression (an indicator of Sp1 transactivation activity). Inhibition of LISPDE activity using a selective LISPDE inhibitor mimicked the effects of NF-κB blockade. Pretreatment of LPS-challenged WT mice with a selective LISPDE inhibitor increased nuclear Sp1 protein content, restored Sp1 DNA binding activity and reversed eNOS protein down-regulation in lungs. Enhancing tissue level of Sp1 activity by inhibiting NF-κB-mediated Sp1 down-regulation increased tissue level of IL-10 and decreased tissue level of TNF- αin the lungs.ConclusionsNF-κB signaling mediates LPS-induced down-regulation of Sp1 activity. Activation of NF-κB pathway suppresses Sp1 activity and Sp1-mediated anti-inflammatory signals. Conversely, Sp1 signaling counter-regulates NF-κB-mediated inflammatory response. Crosstalk between NF-κB and Sp1 pathways regulates the balance between pro- and anti-inflammatory cytokines.

Project description:Introduction The impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined. Methods Lipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying. Results Upon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs. Conclusion Our findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

Project description:Acute respiratory distress syndrome (ARDS), a devastating complication of numerous conditions, is often associated with high mortality. It is well known that endothelial cell (EC) damage and inflammation are vital processes in the pathogenesis of ARDS. Nevertheless, the mechanisms of EC damage are largely unknown. In the present study, we investigated the role of pyroptosis in the initiation of ARDS and demonstrated that endothelial pyroptosis might play a pivotal role in the pathophysiology of ARDS. Metformin, an antidiabetic drug, exhibited a protective effect in lipopolysaccharide (LPS)-induced lung injury, and we hypothesized that metformin alleviated LPS-induced lung injury via inhibiting ECs pyroptosis. In vivo, male ICR mice were intratracheally injected with LPS, and metformin was previously administered intraperitoneally. Morphological properties of lung tissues were detected. We showed that metformin inhibited NLRP3 inflammasome activation and NLRP3-stimulated pyroptosis induction, as shown by decreased levels of cleaved caspase-1, N-terminal fragment of GSDMD, and protein contents of IL-1β in lung tissues of mice exposed to LPS. LPS-induced expression of vascular adhesion molecules was also reduced after the treatment with metformin. In vitro, exposure of pulmonary ECs to LPS resulted in increased expression of NLRP3 and pyroptosis-associated indicators. By inhibiting the expression of NLRP3 with NLRP3 inhibitor MCC950, pyroptosis-related markers and vascular adhesion molecules were ameliorated. Moreover, metformin treatment significantly inhibited the NF-κB signaling pathway and increased the expression of sirtuin 1 (SIRT1) both in LPS-stimulated lung tissues and pulmonary ECs. Administration of the selective SIRT1 inhibitor nicotinamide significantly reversed the protective effect of metformin against endothelial pyroptosis and lung injury in LPS-treated ECs and LPS-induced acute lung injury (ALI). Thus, these findings demonstrated that metformin alleviated LPS-induced ALI by inhibiting NF-κB-NLRP3-mediated ECs pyroptosis, possibly by upregulating the expression of SIRT1.

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NF-?B-to-AP-1 switch: a mechanism regulating transition from endothelial barrier injury to repair in endotoxemic mice.

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NF-κB-to-AP-1 switch: a mechanism regulating transition from endothelial barrier injury to repair in endotoxemic mice.

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