Cathepsin B-Mediated NLRP3 Inflammasome Formation and Activation in Angiotensin II -Induced Hypertensive Mice: Role of Macrophage Digestion Dysfunction

Abstract

Background/Aims: Angiotensin II (Ang II) is an octapeptide hormone that plays a significant role in mediating hypertension. Although hypertension is considered a chronic inflammatory disease, the molecular basis of the sterile inflammatory response involved in hypertension remains unclear. Methods: We investigated the role of macrophage NLRP3 inflammasomes in engulfing and digesting microbes, a key macrophage function, and in early onset of hypertension-associated macrophage injury using biochemical analyses, gene silencing, molecular biotechnology, immunofluorescence, and microbiology. Results: Ang II stimulation decreased nitric oxide (NO) release and macrophage digestion in cultured THP-1 cells and markedly increased NLRP3 inflammasome formation and activation. NO release and macrophage digestion were restored by NLRP3 inflammasome inhibition with isoliquiritigenin and gene silencing. This Ang II-induced upregulation of NLRP3 inflammasomes in macrophages was attributed to lysosomal damage and release of cathepsin B. Mechanistically, losartan, a nonpeptide Ang II receptor antagonist, decreased Ang II-induced NLRP3 inflammasome activation, lysosomal membrane permeability, lysosomal cathepsin B release, and macrophage digestion dysfunction. Similarly, Ang II-induced macrophage microbe digestion and NO production, which were blocked by ATI gene silencing. In addition, in vivo experiments showed that the bacteria scavenging function was clearly decreased in macrophages from Ang II-induced hypertensive mice. Conclusion: Angiotensin II enhances lysosomal membrane permeabilization and the consequent release of lysosomal cathepsin B, resulting in activation of the macrophage NLRP3 inflammasome. This may contribute to NO mediation of dysfunction in digesting microbes.

The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process

“…Thus, fibrillar Aβ interacts with TLRs to promote the transcriptional priming of the NLRP3 inflammasome through NF-κB activation. Then, ROS, cathepsin B, and other metabolites released upon lysosomal damage induce the activation and oligomerization of the inflammasome [ 221 , 222 , 223 ]. NLRP3-mediated IL-1β production triggers the release of downstream inflammatory cytokines and neurotoxic factors.…”

Sinomenine hydrochloride ameliorates dextran sulfate sodium‑induced colitis in mice by modulating the gut microbiota composition whilst suppressing the activation of the NLRP3 inflammasome

“…The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multi-protein complex comprising NLRP3, PYD and CARD domains that contain pro-caspase-1, which has been found to serve a role in UC ( 8 ). The NLRP3 inflammasome is stimulated by a diverse series of agonists (such as ATP and UV radiation, and pattern-associated molecular patterns derived from bacteria, virus, fungus, and protozoa) ( 9 ), before activates caspase-1, which results in the maturation of the proinflammatory cytokine IL-1β ( 10 ). It was previously reported that the activation of NLRP3 inflammasome served an inflammatory role in dextran sulfate sodium (DSS)-induced colitis ( 11 ).…”

Effects of irbesartan on myocardial injury in diabetic rats: The role of NLRP3/ASC/Caspase-1 pathway

“…Ang II can cause NLRP3 inflammasome activation by promoting endoplasmic reticulum stress and release of cathepsin B. 32,33 Activated NLRP3 inflammasome causes cell damage, mitochondrial dysfunction, smooth muscle phenotypic transformation and vascular remodeling, causing abnormalities in tissues and organs. 34,35 Some studies have shown that the effects of angiotensin-converting enzyme inhibitors or ARBs on diabetes may be achieved through the Caspase pathway.…”