Nod1, short for Nucleotide-binding oligomerization domain 1, is an intracellular pattern recognition receptor [1,2,4,5,6]. It detects injury signals, bacterial peptidoglycan-conserved motifs, and initiates inflammatory responses, host defense, and also serves as a metabolic mediator [1,2,4]. Nod1 activates the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways by engaging the adaptor protein RIP2, which is crucial for innate and potentially adaptive immunity [6]. Genetic models, such as knockout (KO) mouse models, have been valuable in studying its functions.

In KO mouse models, Nod1-dependent NF-κB activation was found to be essential for hematopoietic stem cell specification. In the absence of Nod1 and its downstream kinase Ripk2, hemogenic endothelial programming fails, preventing HSPC specification [3]. Nod1-deficient models are also protected from high-fat diet (HFD)-induced insulin resistance, indicating its role in the development of insulin resistance [5]. In hepatocellular carcinoma, activation of Nod1 in tumor-associated macrophages augments CD8+ T cell-mediated antitumor immunity, and its expression in TAMs correlates positively with improved prognosis and responses to anti-PD-1 treatments [7].

In summary, model-based research has revealed that Nod1 is vital in processes like hematopoietic stem cell specification, metabolic regulation such as insulin resistance, and in modulating antitumor immunity. Nod1 KO models have contributed significantly to understanding its role in diseases related to hematopoiesis, metabolism, and cancer, providing insights that could potentially lead to new therapeutic strategies for these disease areas.

References:

1. Trindade, Bruno C, Chen, Grace Y. 2020. NOD1 and NOD2 in inflammatory and infectious diseases. In Immunological reviews, 297, 139-161. doi:10.1111/imr.12902. https://pubmed.ncbi.nlm.nih.gov/32677123/

2. Caruso, Roberta, Warner, Neil, Inohara, Naohiro, Núñez, Gabriel. 2014. NOD1 and NOD2: signaling, host defense, and inflammatory disease. In Immunity, 41, 898-908. doi:10.1016/j.immuni.2014.12.010. https://pubmed.ncbi.nlm.nih.gov/25526305/

3. Cheng, Xiaoyi, Barakat, Radwa, Pavani, Giulia, Campbell, Clyde A, Espin-Palazon, Raquel. 2023. Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases. In Nature communications, 14, 7668. doi:10.1038/s41467-023-43349-1. https://pubmed.ncbi.nlm.nih.gov/37996457/

4. Tang, Ruobing, Xie, Chunguang, Zhang, Xiyu. 2025. NOD1: a metabolic modulator. In Frontiers in endocrinology, 15, 1484829. doi:10.3389/fendo.2024.1484829. https://pubmed.ncbi.nlm.nih.gov/39906040/

5. Rivers, Sydney L, Klip, Amira, Giacca, Adria. . NOD1: An Interface Between Innate Immunity and Insulin Resistance. In Endocrinology, 160, 1021-1030. doi:10.1210/en.2018-01061. https://pubmed.ncbi.nlm.nih.gov/30807635/

6. Wang, Dongjie. 2022. NOD1 and NOD2 Are Potential Therapeutic Targets for Cancer Immunotherapy. In Computational intelligence and neuroscience, 2022, 2271788. doi:10.1155/2022/2271788. https://pubmed.ncbi.nlm.nih.gov/36262606/

7. Zhang, Feng, Jiang, Qiuyu, Cai, Jialiang, Dong, Ling, Zhang, Si. 2024. Activation of NOD1 on tumor-associated macrophages augments CD8+ T cell-mediated antitumor immunity in hepatocellular carcinoma. In Science advances, 10, eadp8266. doi:10.1126/sciadv.adp8266. https://pubmed.ncbi.nlm.nih.gov/39356756/