Hdc, short for Histidine decarboxylase, is a rate-limiting enzyme for histamine synthesis. Histamine, synthesized by Hdc, functions as a critical mediator of anaphylaxis, a neurotransmitter, and a regulator of gastric acid secretion. The Hdc gene has been studied using gene knockout models to understand its role in various biological processes and disease conditions [3].

In Hdc deficiency (Hdc -/-) mouse models, neutrophils are disorderly recruited into the ischemic injured area of the myocardium. Hdc -/- neutrophils show attenuated adhesion but enhanced migration and augmented ROS/neutrophil extracellular traps (NETs) production, which promotes cardiomyocyte death and cardiac fibroblast proliferation/migration. Also, protein arginine methyltransferase 1 (PRMT1) is increased in these neutrophils [1]. In Hdc knockout (Hdc -/-) mice, cisplatin-induced ototoxicity is exacerbated due to histamine deficiency, which accelerates hair cell ferroptosis through the H1R pathway [6]. An inactivating mutation in the Hdc gene, as recapitulated in Hdc knockout mice, is associated with Tourette syndrome-like phenotypes, including white matter abnormalities in the dorsal striatum, potentially due to abnormal myelination [5]. In a comorbid mouse model of ovarian cancer and depression, chronic stress downregulates Hdc expression, promoting ovarian cancer progression via the IL-6/STAT3/S100A9 pathway [4]. Hdc-expressing myeloid-derived suppressor cells promote basal-like transition and metastasis of breast cancer by aberrantly activating Wnt/β-catenin signaling in CK14+ malignant cells [2].

In conclusion, Hdc plays essential roles in multiple biological processes and disease conditions. Gene knockout mouse models have been crucial in revealing its functions, particularly in cardiovascular diseases, ototoxicity, neurodevelopmental syndromes, ovarian cancer, and breast cancer. These findings provide new biomarkers and targets for identifying and tuning the detrimental immune state in related diseases.

References:

1. Zhang, Zhiwei, Ding, Suling, Wang, Zhe, Yang, Xiangdong, Ge, Junbo. 2021. Prmt1 upregulated by Hdc deficiency aggravates acute myocardial infarction via NETosis. In Acta pharmaceutica Sinica. B, 12, 1840-1855. doi:10.1016/j.apsb.2021.10.016. https://pubmed.ncbi.nlm.nih.gov/35847488/

2. Chen, Na, Feng, Qiong, Deng, Jun, Hu, Jin-Ping, Deng, Huan. 2020. Hdc-expressing myeloid-derived suppressor cells promote basal-like transition and metastasis of breast cancer. In International journal of clinical and experimental pathology, 13, 1431-1443. doi:. https://pubmed.ncbi.nlm.nih.gov/32661481/

3. Li, Yapeng, Gao, Junfeng, Zhao, Dianzheng, Finkelman, Fred D, Huang, Hua. 2023. The Hdc GC box is critical for Hdc gene transcription and histamine-mediated anaphylaxis. In The Journal of allergy and clinical immunology, 152, 195-204.e3. doi:10.1016/j.jaci.2023.01.031. https://pubmed.ncbi.nlm.nih.gov/36804390/

4. Chen, Zhicong, Cao, Jinming, Xiao, Zhijun, Zhou, Ting, Xu, Feng. 2024. HDC downregulation induced by chronic stress promotes ovarian cancer progression via the IL-6/STAT3/S100A9 pathway. In Frontiers in pharmacology, 15, 1485885. doi:10.3389/fphar.2024.1485885. https://pubmed.ncbi.nlm.nih.gov/39720595/

5. Jindachomthong, Kantiya, Yang, Chengran, Huang, Yuegao, Frick, Luciana, Pittenger, Christopher. 2022. White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology. In Frontiers in molecular neuroscience, 15, 1037481. doi:10.3389/fnmol.2022.1037481. https://pubmed.ncbi.nlm.nih.gov/36504678/

6. Wu, Daquan, Zhu, Baoling, Yang, Xiyang, Yang, Xiangdong, Huang, Xinsheng. 2024. Histamine deficiency exacerbates cisplatin-induced ferroptosis in cochlea hair cells of HDC knockout mice. In International immunopharmacology, 138, 112639. doi:10.1016/j.intimp.2024.112639. https://pubmed.ncbi.nlm.nih.gov/38972209/