Nlrp3-KO Mouse

NLRP3, also known as NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3, is a crucial 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 plays a significant role in the inflammatory response, being activated by various host “danger” situations like infection and metabolic dysregulation [1,2].

Mitophagy/autophagy blockade leads to the accumulation of damaged mitochondria that generate reactive oxygen species (ROS), which in turn activates the NLRP3 inflammasome [1]. Different NLRP3 stimuli cause the disassembly of the trans-Golgi network (TGN), and NLRP3 is recruited to the dispersed TGN through an ionic bond with phosphatidylinositol-4-phosphate (PtdIns4P), leading to its aggregation and downstream signaling activation [3]. Palmitoylation of NLRP3 Cys126 by ZDHHC7 promotes NLRP3-mediated inflammasome activation both in macrophages and in vivo [4].

The NLRP3 inflammasome is involved in various disease conditions. For example, in inflammatory root resorption, force-pre-treated human periodontal ligament cells (hPDLCs) promote M1 macrophage polarization and the production of NLRP3, caspase-1, and IL-1β in M1 macrophages, and this can be inhibited by an NLRP3 inflammasome inhibitor [5]. In acute liver injury, the aberrant activation of the NLRP3 inflammasome plays an important role, and it is closely related to programmed cell death [6]. Also, NLRP3 activation is associated with many cardiovascular diseases and is a potential target for treatment [7]. In COVID-19, NLRP3 activation may contribute to the intense and rapid stimulation of the innate immune response [8].

In conclusion, NLRP3 is essential for the activation of the NLRP3 inflammasome and subsequent inflammatory responses. Through model-based research, especially in conditions like liver injury, inflammatory root resorption, cardiovascular diseases, and COVID-19, the role of NLRP3 in disease-associated inflammation has been revealed. Understanding NLRP3 function provides potential therapeutic strategies for these diseases.

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. Zhang, Jie, Liu, Xinqiang, Wan, Chunyan, Zhang, Yipeng, Jiang, Chunmiao. 2020. NLRP3 inflammasome mediates M1 macrophage polarization and IL-1β production in inflammatory root resorption. In Journal of clinical periodontology, 47, 451-460. doi:10.1111/jcpe.13258. https://pubmed.ncbi.nlm.nih.gov/31976565/

6. 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/

7. 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/

8. 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/