Stimulation of soluble guanylate cyclase exerts anti-inflammatory actions in the liver through a VASP/NF-kB/NLRP3 inflammasome circuit

Soluble guanylate cyclase (sGC) catalyzes the conversion of GTP into cyclic guanosine-3',5’-monophosphate (cGMP), a key second messenger in cell signaling and tissue homeostasis. We and others recently demonstrated that sGC stimulation is associated with a remarkable anti-inflammatory effect in the liver of mice experimentally induced to nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms of action underlying the anti-inflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted anti-inflammatory and anti-fibrotic actions in mice fed with choline-deficient L-amino acid-defined high-fat diet (CDAHFD), an optimized experimental model of NASH. The anti-inflammatory effect of PRL 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 anti-inflammatory effect was also associated with a remarkable suppression of hepatic levels of IL-1β, NLPR3, ASC and active cleaved-Caspase-1, which are components of the NLRP3 inflammasome. In vitro, in Kupffer cells challenged with the classical inflammasome model of LPS plus ATP, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the PKG-mediated phosphorylation of the VASP Ser239 residue, which in turn, reduced NF- κB activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-Caspase-1 levels independently of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts anti-inflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-kB/NLRP3 inflammasome circuit. Transcriptomic analysis from 8 control mouse (C) and 8 samples from nonalcoholic steatohepatitis (NASH) mouse model (CD)