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Ouabain alleviates Mycobacterium abscessus-triggered inflammatory responses through dual regulation of NLRP3 inflammasome activity and M1 macrophage polarization

ABSTRACT: Mycobacterium abscessus (M. abscessus), one of the most drug-resistant and difficult-to-treat pathogens, primarily causes chronic pulmonary inflammation in humans. The cardiac glycoside ouabain has demonstrated broad-spectrum anti-inflammatory properties in multiple disease models. However, its therapeutic potential against M. abscessus-induced pulmonary inflammation remains unexplored. In this study, we aim to investigate the role of ouabain on M. abscessus-induced inflammation. Our results demonstrated that ouabain remarkably attenuated M. abscessus-mediated inflammatory responses by decreasing the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. H&E results showed that intraperitoneal administration of ouabain alleviated M. abscessus-induced pulmonary inflammation and injury. Transcriptomic analysis and qPCR results further revealed that ouabain treatment significantly suppressed the upregulation of pro-inflammatory cytokines induced by M.abscessus and downregulated NLRP3 inflammasome expression in vivo. In vitro experiments further confirmed that ouabain treatment effectively suppressed both NLRP3 inflammasome activation and M1 macrophage polarization. Collectively, these findings suggested that ouabain alleviated M. abscessus-induced pulmonary inflammation through dual mechanisms: inhibition of NLRP3 inflammasome activation and modulation of M1 macrophage polarization. This work highlights ouabain’s potential as a therapeutic candidate for combating M. abscessus infections.

ORGANISM(S): Mus musculus

PROVIDER: GSE301915 | GEO | 2025/09/03

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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Ouabain alleviates Mycobacterium abscessus-triggered inflammatory responses through dual regulation of NLRP3 inflammasome activity and M1 macrophage polarization

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