DC ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension.
DC ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension.
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DOI：
10.1161/circresaha.122.320818
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发表时间：
2022-08-05
影响因子：
20.1
通讯作者：
Kirabo, Annet
中科院分区：
文献类型：
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作者：
Pitzer, Ashley;Elijovich, Fernando;Laffer, Cheryl L.;Ertuglu, Lale A.;Sahinoz, Melis;Saleem, Mohammad;Krishnan, Jaya;Dola, Thanvi;Aden, Luul A.;Sheng, Quanhu;Raddatz, Michael A.;Wanjalla, Celestine;Pakala, Suman;Davies, Sean S.;Patrick, David M.;Kon, Valentina;Ikizler, T. Alp;Kleyman, Thomas;Kirabo, Annet
Salt sensitivity of blood pressure is an independent predictor of cardiovascular morbidity and mortality. The exact mechanism by which salt intake increases blood pressure and cardiovascular risk is unknown. We previously found that sodium entry into antigen-presenting cells (APCs) via the amiloride-sensitive epithelial sodium channel ENaC leads to the formation of isolevuglandins (IsoLGs) and release of pro-inflammatory cytokines to activate T cells and modulate salt-sensitive hypertension. In the current study, we hypothesized that ENaC-dependent entry of sodium into APCs activates the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via IsoLG formation leading to salt-sensitive hypertension. We performed RNAseq on human monocytes treated with elevated sodium in vitro and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) analysis of peripheral blood mononuclear cells (PBMCs) from participants rigorously phenotyped for salt sensitivity of blood pressure using an established inpatient protocol. To determine mechanisms, we analyzed inflammasome activation in mouse models of deoxycorticosterone acetate (DOCA)-salt-induced hypertension as well as salt-sensitive mice with ENaC inhibition or expression, IsoLG scavenging, and adoptive transfer of wildtype dendritic cells into NLRP3 deficient mice. We found that high levels of salt exposure upregulates the NLRP3 inflammasome, pyroptotic and apoptotic caspases, and IL-1β transcription in human monocytes. CITE-seq revealed that components of the NLRP3 inflammasome and activation marker IL-1β dynamically vary with changes in salt loading/depletion. Mechanistically, we found that sodium-induced activation of the NLRP3 inflammasome is ENaC and IsoLG dependent. NLRP3 deficient mice develop a blunted hypertensive response to elevated sodium, and this is restored by the adoptive transfer of NLRP3 replete APCs. These findings reveal a mechanistic link between ENaC, inflammation, and salt-sensitive hypertension involving NLRP3 inflammasome activation in APCs. APC activation via the NLRP3 inflammasome can serve as a potential diagnostic biomarker for salt-sensitivity of blood pressure.
