Nlrp3-KO Mouse

NLRP3, also known as NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3, is a key component of the NLRP3 inflammasome. The NLRP3 inflammasome is a multi-protein signaling complex that triggers the activation of inflammatory caspases and the maturation of interleukin-1β. It is involved in the body's response to various "danger" situations such as infection and metabolic dysregulation, and plays a crucial role in the innate immune response [2].

Mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, which in turn activates the NLRP3 inflammasome. Inhibition of the voltage-dependent anion channel, which dysregulates mitochondrial activity, suppresses both ROS generation and inflammasome activation, indicating that NLRP3 inflammasome senses mitochondrial dysfunction [1]. Different NLRP3 stimuli lead to the disassembly of the trans-Golgi network (TGN). NLRP3 is recruited to the dispersed TGN through ionic bonding, which then serves as a scaffold for NLRP3 aggregation and downstream signaling activation [3]. ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes NLRP3 activation both in macrophages and in vivo by facilitating its localization on the TGN and dispersed TGN, which is essential for the recruitment and oligomerization of the adaptor ASC [4]. In various diseases, NLRP3 inflammasome activation has been implicated. For example, in acute liver injury, its aberrant activation is important and is linked to programmed cell death [5]. In cardiovascular diseases, NLRP3 activation can regulate cell survival through caspase-1 and gasdermin-D, and NLRP3 inhibitors may target its deleterious effects [6]. In COVID-19, NLRP3 activation is involved in the intense innate immune response, leading to cytokine release and pyroptosis [7].

In conclusion, NLRP3 is central to the activation of the NLRP3 inflammasome, which is a key player in the innate immune response. Through model-based research, NLRP3 has been shown to be involved in multiple disease-related processes, including those in the liver, cardiovascular system, and during viral infections like COVID-19. Understanding NLRP3 function through gene-knockout or conditional-knockout mouse models provides insights into the underlying mechanisms of these diseases, offering potential therapeutic targets for treatment [1,4,5,6,7].

References:

1. Zhou, Rongbin, Yazdi, Amir S, Menu, Philippe, Tschopp, Jürg. 2010. A role for mitochondria in NLRP3 inflammasome activation. In Nature, 469, 221-5. doi:10.1038/nature09663. https://pubmed.ncbi.nlm.nih.gov/21124315/

2. Jo, Eun-Kyeong, Kim, Jin Kyung, Shin, Dong-Min, Sasakawa, Chihiro. 2015. Molecular mechanisms regulating NLRP3 inflammasome activation. In Cellular & molecular immunology, 13, 148-59. doi:10.1038/cmi.2015.95. https://pubmed.ncbi.nlm.nih.gov/26549800/

3. Chen, Jueqi, Chen, Zhijian J. 2018. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. In Nature, 564, 71-76. doi:10.1038/s41586-018-0761-3. https://pubmed.ncbi.nlm.nih.gov/30487600/

4. Yu, Tao, Hou, Dan, Zhao, Jiaqi, Linder, Maurine E, Lin, Hening. 2024. NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation. In Cell reports, 43, 114070. doi:10.1016/j.celrep.2024.114070. https://pubmed.ncbi.nlm.nih.gov/38583156/

5. Yu, Chaoqun, Chen, Peng, Miao, Longyu, Di, Guohu. 2023. The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury. In International journal of molecular sciences, 24, . doi:10.3390/ijms24043067. https://pubmed.ncbi.nlm.nih.gov/36834481/

6. Mezzaroma, Eleonora, Abbate, Antonio, Toldo, Stefano. 2021. NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases. In Molecules (Basel, Switzerland), 26, . doi:10.3390/molecules26040976. https://pubmed.ncbi.nlm.nih.gov/33673188/

7. Yin, Maureen, Marrone, Laura, Peace, Christian G, O'Neill, Luke A J. . NLRP3, the inflammasome and COVID-19 infection. In QJM : monthly journal of the Association of Physicians, 116, 502-507. doi:10.1093/qjmed/hcad011. https://pubmed.ncbi.nlm.nih.gov/36661317/