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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE154892 | GEO | 2020/12/01

REPOSITORIES: GEO

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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

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