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Nuclear Receptor Coactivator 6 is a Critical Regulator of NLRP3 Inflammasome Activation and Gouty Arthritis

ABSTRACT: Transcriptional coactivators regulate the rate of gene expression in the nucleus, but their role in the extranuclear sites is largely unknown. Here, we demonstrated that nuclear receptor coactivator 6 (NCOA6) translocated to the cytoplasm, then was incorporated to NLRP3 inflammasome complex, and acquired a new function of “activation of inflammation and innate immune response”, beyond its original function of nuclear coactivation, in monocytes and macrophages. Mechanistically, cytoplasmic NCOA6 directly interacted with NACHT domain of NLRP3 and then promoted NLRP3 activity. Genetic ablation of Ncoa6 substantially attenuated severity of mouse models of two NLRP3-dependent diseases, folic-induced acute tubular necrosis and crystal-induced arthritis in mice. Consistent with these findings, NCOA6 was highly expressed in macrophages of gout patients and its signature was significantly enriched in the gout macrophages in transcriptome profiling. Conclusively, NCOA6 is a critical regulator of the NLRP3 inflammasome activation and therefore a promising target for NLRP3-dependent diseases, including gout.

ORGANISM(S): Mus musculus

PROVIDER: GSE207875 | GEO | 2024/03/05

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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Nuclear Receptor Coactivator 6 is a Critical Regulator of NLRP3 Inflammasome Activation and Gouty Arthritis

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