Abstract
Cell inflammation and death are closely linked processes contributing to endothelial
dysfunction, which plays a critical role in atherogenesis. Activation of the NLRP3
inflammasome causes pyroptosis, the Gasdermin D (GSDMD)-mediated inflammatory cell
death. The non-canonical NF-κB pathway has been implicated in inflammation; however,
its role in NLRP3 inflammasome-mediated endothelial dysfunction has not been investigated.
This study investigated a role for the non-canonical NF-κB pathway in regulating endothelial
pyroptosis as it relates to atherogenesis. Immunohistochemistry indicated inflammasome
activation in the endothelial cells (EC) of human atherosclerotic arteries. Flow cytometry
and Western blot analysis revealed that oxidized low-density lipoprotein (oxLDL) activated
the NLRP3 inflammasome, concomitant with the activation of non-canonical NF-κB in
primary human aortic EC. Interference of NF-κB inducing kinase (NIK), the key regulator
of the non-canonical pathway, significantly attenuated oxLDL- or LPS/ATP-induced NLRP3
inflammasome activation, pyroptosis, IL-1β, and IL-18 secretion. In contrast, overexpression
of NIK exacerbated these responses. Chromatin immunoprecipitation revealed that activation
of the non-canonical NF-κB pathway upregulated the transcription factor IRF-1 through
RelB/p52 binding to its promoter region at -782/-770. In addition to the known target
CASP1, RNA sequencing further identified GSDMD as a target gene of IRF-1. IRF-1 but not RelB/p52 interacted with the GSDMD promoter at -526/-515 and the CASP1 promoter at -11/10 to promote the expression and CASP1-mediated activation of GSDMD. Consistent with the observations in cultured endothelium,
endothelial-specific deficiency of NIK or IRF-1 attenuated atherosclerosis in high-fat
diet-fed Apoe-null mice. These data demonstrate that the non-canonical NF-κB pathway contributes
to NLRP3 inflammasome-mediated endothelial pyroptosis and the development of atherosclerosis
through GSDMD activation in a manner dependent on IRF-1. Further investigation may
facilitate the identification of specific therapeutic targets for atherosclerotic
heart diseases.
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Article Info
Publication History
Published online: November 12, 2022
Accepted:
November 1,
2022
Received in revised form:
October 7,
2022
Received:
August 13,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
