Hrh4, the histamine H4 receptor gene, is one of four known histamine receptor genes. It is expressed in various cell types such as neurons, vascular endothelial cells, eosinophils, and Leydig cells [3,6,8]. HRH4 is involved in multiple biological processes, including inflammation, cell proliferation, and steroidogenesis. It is also potentially associated with pathways related to epithelial-to-mesenchymal transition (EMT) [1].

In non-small cell lung cancer (NSCLC), the rs11662595 mutation in HRH4 leads to its dysfunction, facilitating EMT progress, cell proliferation, and invasion. This mutation also attenuates the anti-EMT effects of HRH4 agonist in nu/nu mice [1]. In ankylosing spondylitis, specific HRH4 polymorphisms (rs657132 AA genotype and A-A haplotype in rs8088140-rs657132) are associated with increased disease susceptibility [2]. In colorectal and gastric carcinomas, reduced HRH4 expression is observed, which may influence tumor growth and progression [4,7]. In the context of allergic inflammation in the esophagus, esophageal eosinophils express HRH4 and exist as two populations, with one being ready to interact with diverse cell types [3]. In Leydig cells, HRH4 activation inhibits steroidogenesis and cell proliferation [8]. In diabetic retinopathy and age-related macular degeneration, HRH4 antagonists show potential as preventive and therapeutic agents without causing retinal toxicity [5,6].

In conclusion, HRH4 plays a crucial role in multiple biological processes and disease conditions. Studies using genetic models, although not always explicitly KO/CKO mouse models in the provided references, have revealed its functions in inflammation, cell growth, and disease progression in areas such as cancer, autoimmune diseases, and eye diseases. These findings provide potential biomarker and therapeutic targets for related diseases.

References:

1. Cai, Wen-Ke, Zhang, Jia-Bin, Chen, Ji-Hui, Xu, Gui-Li, He, Gong-Hao. 2017. The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer. In Biochimica et biophysica acta. Molecular basis of disease, 1863, 2954-2963. doi:10.1016/j.bbadis.2017.08.018. https://pubmed.ncbi.nlm.nih.gov/28847511/

2. Ran, Bo, Wang, Yongcheng, Zhang, Yonggang, Mao, Keya, Wang, Yan. 2015. Association between HRH4 polymorphisms and ankylosing spondylitis susceptibility. In International journal of clinical and experimental pathology, 8, 15265-9. doi:. https://pubmed.ncbi.nlm.nih.gov/26823878/

3. Ben-Baruch Morgenstern, Netali, Rochman, Mark, Kotliar, Michael, Barski, Artem, Rothenberg, Marc E. 2024. Single-cell RNA-sequencing of human eosinophils in allergic inflammation in the esophagus. In The Journal of allergy and clinical immunology, 154, 974-987. doi:10.1016/j.jaci.2024.05.029. https://pubmed.ncbi.nlm.nih.gov/38871184/

4. Fang, Zhengyu, Yao, Wantong, Xiong, Yi, Nie, Liping, Wan, Jun. 2011. Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression. In BMC cancer, 11, 195:1-11. doi:10.1186/1471-2407-11-195. https://pubmed.ncbi.nlm.nih.gov/21609450/

5. Kwon, Jung Won, Lee, Kihwang, Kim, Sang Wha, Che, Jeong-Hwan, Seok, Seung Hyeok. 2024. Therapeutic potential of histamine H4 receptor antagonist as a preventive treatment for diabetic retinopathy in mice. In Scientific reports, 14, 22664. doi:10.1038/s41598-024-72166-9. https://pubmed.ncbi.nlm.nih.gov/39349555/

6. Kaneko, Hiroki. . [Histamime Receptor H4 as a New Therapeutic Target for Age-related Macular Degeneration]. In Nippon Ganka Gakkai zasshi, 120, 747-53. doi:. https://pubmed.ncbi.nlm.nih.gov/30074739/

7. Zhang, Chao, Xiong, Yi, Li, Jiana, Li, Manhui, Fang, Zhengyu. 2012. Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression. In PloS one, 7, e31207. doi:10.1371/journal.pone.0031207. https://pubmed.ncbi.nlm.nih.gov/22363581/

8. Abiuso, Adriana María Belén, Berensztein, Esperanza, Pagotto, Romina María, Pignataro, Omar Pedro, Mondillo, Carolina. 2014. H4 histamine receptors inhibit steroidogenesis and proliferation in Leydig cells. In The Journal of endocrinology, 223, 241-53. doi:10.1530/JOE-14-0401. https://pubmed.ncbi.nlm.nih.gov/25253872/