Molecular Network of NLRP3 Inflammasome Activation-Responsive Genes in a Human Monocyte Cell Line

Research Article

Austin J Clin Immunol. 2014;1(4): 1017.

Molecular Network of NLRP3 Inflammasome Activation-Responsive Genes in a Human Monocyte Cell Line

Natsuki Kawana, Yoji Yamamoto, Yoshihiro Kino and Jun-ichi Satoh*

Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Japan

*Corresponding author: Jun-ichi Satoh, Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Received: May 05, 2014; Accepted: June 11, 2014; Published: June 13, 2014


Background: 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-1β (IL-1β) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first ““priming” signal enhances gene expression of inflammasome components. The second “activation” signal 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.

Methods: 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.

Results: 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 IκB 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.

Conclusion: NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation.

Keywords: Mast cells; Autoimmune diseases


Inflammasome serves as a multi molecular signaling complex involved in activation of Caspase-1 (CASP1) and maturation of interleukin-1β (IL-1β) and IL-18 [1,2]. A wide variety of exogenous and endogenous stimuli, characterized by microbe-derived Pathogen- Associated Molecular Patterns (PAMPs) and host- or environment-derived Danger-Associated Molecular Patterns (DAMPs), are recognized by an intracellular sensor called the NOD-like Receptors (NLRs), resulting in rapid induction of inflammasome formation by ordered assembly of self-oligomerizing components.

Among various classes of inflammasome, the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome has been most intensively studied. It is composed of NLRP3, the adaptor molecule named apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the precursor form of the cysteine protease pro-CASP1 [1,2]. NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain essential for activation of the signaling complex via ATP-dependent oligomerization, flanked by a C-terminal Leucine-Rich Repeat (LRR) pivotal for ligand sensing and auto regulation and a N-terminal pyrin (PYD) domain involved in a homotypic protein-protein interaction between NLRP3 and ASC. The molecular interaction of NLRP3 with ASC recruits pro-CASP1 by a homotypic interaction of Caspase Activation and Recruitment (CARD) domains between ASC and pro-CASP1. Subsequently, the proximity-induced pro-CASP1 oligomerization causes autocatalytic activation of CASP1, resulting in processing of pro-IL-1β or pro- IL-18 into biologically active IL-1β and IL-18. Both of them act as a central regulator for induction of cytokines and chemokines that amplify inflammation by recruiting immune effector cells.

The activation of NLRP3 inflammasome requires two-step signals (Figure 1) [3,4]. The first “priming” signal termed Signal 1, such as microbe-derived Lipo Poly Saccharide (LPS), enhances gene expression of inflammasome components and target proteins via activation of transcription factor nuclear factor-kappa B (NF- κB). The second “activation” signal termed Signal 2 promotes the organized assembly of inflammasome components. The second signal involves three major mechanisms, such as generation of Reactive Oxygen Species (ROS), lysosomal protease leakage, and the potassium efflux [1,2]. Mitochondria often serve as the principal source of ROS. Blockade of mitophagy induces accumulation of ROS-generating mitochondria that activates NLRP3 inflammasome [5]. Furthermore, oxidized mitochondrial DNA directly activates NLRP3 inflammasome following induction of apoptosis [6]. By serving as an inducer of two-step signals, a diverse range of danger signals armed with PAMPs, such as Listeria monocytogenes, Candida albicans, and influenza A virus and those with DAMPs, such as amyloid-β (Aβ), uric acid and cholesterol crystals, asbestos, silica, alum, hyaluronan, and Adenosine 5’-Triphosphate (ATP), promptly activate the NLRP3 inflammasome [7,8].