Nlrp12, also known as nucleotide-binding leucine-rich repeat-containing receptor 12, is a cytoplasmic sensor belonging to the NLR family. It contains an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat. Nlrp12 plays a crucial role in innate immunity and inflammation, regulating multiple signaling pathways such as MyD88-and TRIF-dependent pathways, and is involved in inflammasome and PANoptosome formation [2,5].

Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model, identifying NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology [1]. In Nlrp12-deficient mice, invasive adenocarcinoma development was associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition, and higher activation of the Wnt/β-catenin pathway, indicating that NLRP12 downregulates β-catenin activation to suppress colorectal tumorigenesis [3]. Pristane-treated Nlrp12 -/- mice showed augmented inflammation and immune responses, and NLRP12-deficient lupus-prone mice had substantial lymphoid hypertrophy, increased autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and kidney function deterioration, suggesting NLRP12's role in lupus nephritis progression [4]. Myeloid-cell-specific Nlrp12-deficient mice displayed a heightened interferon and TNF response and were more resistant to VSV infection, indicating NLRP12 functions as a checkpoint for anti-viral RIG-I activation [6].

In conclusion, Nlrp12 is essential in innate immunity and inflammation, playing roles in various disease-related processes. Findings from gene knockout mouse models have revealed its functions in diseases like acute kidney injury, colorectal cancer, lupus nephritis, and anti-viral responses, highlighting its potential as a drug target for hemolytic and inflammatory diseases [1,3,4,6].

References:

1. Sundaram, Balamurugan, Pandian, Nagakannan, Mall, Raghvendra, Vogel, Peter, Kanneganti, Thirumala-Devi. 2023. NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs. In Cell, 186, 2783-2801.e20. doi:10.1016/j.cell.2023.05.005. https://pubmed.ncbi.nlm.nih.gov/37267949/

2. Tuladhar, Shraddha, Kanneganti, Thirumala-Devi. 2020. NLRP12 in innate immunity and inflammation. In Molecular aspects of medicine, 76, 100887. doi:10.1016/j.mam.2020.100887. https://pubmed.ncbi.nlm.nih.gov/32838963/

3. Khan, Shahanshah, Kwak, Youn-Tae, Peng, Lan, Kanneganti, Thirumala-Devi, Zaki, Hasan. 2023. NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer. In The Journal of clinical investigation, 133, . doi:10.1172/JCI166295. https://pubmed.ncbi.nlm.nih.gov/37581937/

4. Tsao, Yen-Po, Tseng, Fang-Yu, Chao, Chih-Wei, Tsai, Chang-Youh, Chen, Szu-Ting. 2023. NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression. In The Journal of clinical investigation, 133, . doi:10.1172/JCI157272. https://pubmed.ncbi.nlm.nih.gov/36719379/

5. Huang, Lili, Tao, Youli, Wu, Xiping, Shen, Mengya, Zheng, Zhiwei. 2023. The role of NLRP12 in inflammatory diseases. In European journal of pharmacology, 956, 175995. doi:10.1016/j.ejphar.2023.175995. https://pubmed.ncbi.nlm.nih.gov/37572944/

6. Chen, Szu-Ting, Chen, Liang, Lin, Diego Shih-Chieh, Jung, Jae U, Ting, Jenny P-Y. 2019. NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25. In Cell host & microbe, 25, 602-616.e7. doi:10.1016/j.chom.2019.02.013. https://pubmed.ncbi.nlm.nih.gov/30902577/