Macrophage junctional adhesion molecule-like protein (JAML) promotes NLRP3 inflammasome activation in the development of atherosclerosis
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ABSTRACT:
PROVIDER: PRJNA1212144 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32039602_1.fastq.gz | Fastqsanger.gz | |||
| SRR32039602_2.fastq.gz | Fastqsanger.gz | |||
| SRR32039603_1.fastq.gz | Fastqsanger.gz | |||
| SRR32039603_2.fastq.gz | Fastqsanger.gz | |||
| SRR32039604_1.fastq.gz | Fastqsanger.gz |
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Project description:Inflammation plays a crucial role in the progression of atherosclerosis. Junctional adhesion molecule-like protein (JAML), a type-I transmembrane glycoprotein, activates downstream signaling pathways. However, the precise role of macrophage-derived JAML in inflammation and atherosclerosis remains unclear. This study aimed to generate mice with macrophage-specific deletion or overexpression of JAML, with the focus of assessing its impact on macrophage function and elucidating its regulatory mechanism in atherosclerosis. High-throughput data screening was employed to investigate JAML expression in atherosclerosis, and macrophage-specific JAML-knockout and transgenic mice models were utilized to examine the effects of JAML on atherosclerosis. Furthermore, the role of JAML was assessed using Oil Red O staining, RNA-sequencing analysis, and co-immunoprecipitation techniques. Increased JAML expression was observed in macrophages from both mice and patients with atherosclerosis. Macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, whereas macrophage-specific JAML overexpression exacerbated these conditions. Mechanistically, JAML deletion inhibited lipopolysaccharide (LPS) or ox-LDL-induced inflammation by decreasing nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, which consequently suppressed the nuclear factor kappa B (NF-κB) pathway and NLRP3 inflammasome activation. Taken together, these findings demonstrate that macrophage-expressed JAML facilitates the progression of atherosclerosis by activating the NF-κB pathway and NLRP3 inflammasome through nuclear migration and phosphorylation of PKM2. Notably, our study revealed a novel mechanism for the regulation of NLRP3 inflammasome activation in atherosclerosis. Therefore, targeting JAML may be an effective treatment strategy for atherosclerosis, a condition characterized by chronic inflammation.
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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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Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.
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