NLRP6, also known as NOD-like receptor family pyrin domain containing 6, is a member of the NLR family. It acts as a cytosolic innate immune sensor recognizing microbe-associated molecular patterns. NLRP6 is involved in inflammasome activation, regulation of NF-κB and MAPK signaling, antiviral IFN signaling, mucus secretion, and AMP production. It is highly expressed in the intestine and liver, playing a crucial role in regulating inflammation and host defense against microbes [1,4,6,7,9]. Genetic models, such as KO mouse models, are valuable for studying NLRP6's functions.

Nlrp6-deficient mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, as well as in steady state stimulated by intestinal microbiota, indicating the role of NLRP6 in anti-microbial immunity [2]. Nlrp6-/-mice are less susceptible to Listeria monocytogenes infection, associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to these mice restores their susceptibility, revealing an innate immunity pathway triggered by cytosolic LTA sensed by NLRP6 [3]. Loss of NLRP6 suppresses cell proliferation, colony formation, cell migration, and tumour growth in glioblastoma cells in vitro and in vivo, suggesting its role in tumorigenesis [5]. Nlrp6 depletion in mice leads to cognitive defects and hippocampal NSPC loss, indicating its role in maintaining mitochondrial homeostasis of hippocampal NSPCs [8].

In conclusion, NLRP6 is a multifaceted gene involved in anti-microbial immunity, regulation of pathogen infection, tumorigenesis, and maintaining neural stem/progenitor cell homeostasis. Studies using Nlrp6 KO mouse models have significantly contributed to understanding its functions in these disease-related biological processes, providing insights into potential therapeutic targets for related diseases.

References:

1. Li, Runzhi, Zhu, Shu. 2020. NLRP6 inflammasome. In Molecular aspects of medicine, 76, 100859. doi:10.1016/j.mam.2020.100859. https://pubmed.ncbi.nlm.nih.gov/32386845/

2. Shen, Chen, Li, Runzhi, Negro, Roberto, Zhu, Shu, Wu, Hao. 2021. Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome. In Cell, 184, 5759-5774.e20. doi:10.1016/j.cell.2021.09.032. https://pubmed.ncbi.nlm.nih.gov/34678144/

3. Hara, Hideki, Seregin, Sergey S, Yang, Dahai, Chen, Grace Y, Núñez, Gabriel. 2018. The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection. In Cell, 175, 1651-1664.e14. doi:10.1016/j.cell.2018.09.047. https://pubmed.ncbi.nlm.nih.gov/30392956/

4. Zheng, Danping, Kern, Lara, Elinav, Eran. 2020. The NLRP6 inflammasome. In Immunology, 162, 281-289. doi:10.1111/imm.13293. https://pubmed.ncbi.nlm.nih.gov/33314083/

5. Zhi, Feng, Li, Bowen, Zhang, Chuanxia, Peng, Ya, Cui, Jun. 2023. NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis. In Nature communications, 14, 6069. doi:10.1038/s41467-023-41739-z. https://pubmed.ncbi.nlm.nih.gov/37770465/

6. Ghimire, Laxman, Paudel, Sagar, Jin, Liliang, Jeyaseelan, Samithamby. 2020. The NLRP6 inflammasome in health and disease. In Mucosal immunology, 13, 388-398. doi:10.1038/s41385-020-0256-z. https://pubmed.ncbi.nlm.nih.gov/31988468/

7. Venuprasad, K, Theiss, Arianne L. . NLRP6 in host defense and intestinal inflammation. In Cell reports, 35, 109043. doi:10.1016/j.celrep.2021.109043. https://pubmed.ncbi.nlm.nih.gov/33910012/

8. Shen, Jingyan, Xie, Pengfei, Wang, Junhan, Zhou, Feng, Li, Jianmei. 2024. Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy. In Redox biology, 73, 103196. doi:10.1016/j.redox.2024.103196. https://pubmed.ncbi.nlm.nih.gov/38772149/

9. Levy, Maayan, Shapiro, Hagit, Thaiss, Christoph A, Elinav, Eran. 2017. NLRP6: A Multifaceted Innate Immune Sensor. In Trends in immunology, 38, 248-260. doi:10.1016/j.it.2017.01.001. https://pubmed.ncbi.nlm.nih.gov/28214100/