Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit

Abstract

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3′,5′-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.

The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment

“…Furthermore, praliciguat exhibited anti-inflammatory and anti-fibrotic effects in a choline-deficient l -amino acid-defined HFD-induced NASH mouse model. Praliciguat can suppress hepatic levels in NLRP3 inflammasome components, including IL-1 β , NLRP3, caspase-1, and ASC, and exerts anti-inflammatory function in the liver via a vasodilator-stimulated phosphoprotein/NF-κB/NLRP3 circuit ( Flores-Costa et al, 2020 ). Praliciguat can also reduce levels of the active form of cleaved caspase-1 after NLRP3 inflammasome activation, independent of pannexin-1 activity.…”

Inhibition of heat shock protein family A member 8 attenuates spinal cord ischemia–reperfusion injury via astrocyte NF-κB/NLRP3 inflammasome pathway

“…Suppression of NF-κB-mediated inflammatory response ameliorated the hind limb dysfunction of SCII rats [ 12 ]. A study shows that NF-κB-induced oligomerization of NLRP3 with ASC and pro-caspase 1 forms the NLPR3 inflammasome [ 13 ]. Upon stimuli to stress, the activated NLRP3 inflammasome cleaves pro-caspase 1 to the mature caspase-1 p20 and subsequently releases pro-inflammatory factors IL-1β as well as IL-18 [ 13 ].…”

Sacubitril/Valsartan Alleviates Experimental Autoimmune Myocarditis by Inhibiting Th17 Cell Differentiation Independently of the NLRP3 Inflammasome Pathway

“…A few researches have revealed that NF-κB p65 is an important signaling pathway in local inflammatory environment of heart, where it induces differentiation of Th17 cells ( Cheng et al, 2016 ; Sun et al, 2016 ). Another study has revealed that activated sGC inhibits the NF-κB p65 signaling pathway ( Flores-Costa et al, 2020 ). Consequently, we evaluated the effect of activated cardiac NF-κB p65 in myocarditis disease condition.…”