Nlrp12, also known as familial cold autoinflammatory syndrome 2 (FCAS2), is a member of the NLR family. It contains an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat. Nlrp12 can function as an inflammasome component or a negative regulator in innate immune signaling pathways, such as MyD88-and TRIF-dependent pathways, NFκB and MAPK signaling pathways [2]. It is associated with various biological processes like inflammatory cell death, host defense, and maintaining gut homeostasis, and is also related to infectious and inflammatory diseases [1,2]. Genetic models like KO or CKO mouse models are valuable for studying its functions.

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]. Nlrp12-deficient mice showed elevated expression of genes related to proliferation, matrix degradation, and epithelial-mesenchymal transition, along with higher activation of the Wnt/β-catenin pathway in invasive adenocarcinoma development, indicating its role in suppressing colorectal tumorigenesis [3]. Pristane-treated Nlrp12-/-mice had augmented inflammation and immune responses, and NLRP12-deficient lupus-prone mice showed lymphoid hypertrophy, increased autoantibody production, and kidney function deterioration [4].

In conclusion, Nlrp12 is crucial in innate immunity and inflammation. Through model-based research, it has been shown to play important roles in diseases such as hemolytic diseases, colorectal cancer, and lupus nephritis. Gene knockout mouse models have been instrumental in revealing its functions in these disease-related biological processes, providing potential drug targets for these diseases.

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/