Hrh1, the histamine receptor H1, is a crucial component in various biological processes. It mediates the effects of histamine, a molecule involved in immune responses, neurotransmission, and other physiological functions. Activation of Hrh1 can trigger multiple intracellular signaling pathways, influencing cell behavior and function. It has significance in both normal physiological regulation and in the context of disease [3].

In cancer, high levels of histamine and Hrh1 in the tumor microenvironment can lead to T-cell dysfunction. Hrh1-activated macrophages polarize towards an M2-like immunosuppressive phenotype, increasing the expression of the immune checkpoint VISTA, thus rendering T-cells dysfunctional. Hrh1 knockout can reverse macrophage immunosuppression, revitalize T-cell cytotoxic function, and restore immunotherapy response in mice, indicating its role in cancer immunotherapy resistance [1]. In pancreatic cancer, HRH1 blockade upregulates major histocompatibility complex class I (MHC-I) expression in cancer cells via cholesterol biosynthesis signaling. In an orthotopic model, combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T-cell penetration and efficacy, overcoming resistance to immune checkpoint blockade therapy [2]. In zebrafish, hrh1 -/- larvae showed transient abnormal expression of important neurodevelopmental markers and a reduction in the number of tyrosine hydroxylase 1 (Th1)-positive cells and hypocretin (hcrt)-positive cells. Adult hrh1 -/- fish displayed impaired sociability and anxious-like behavior [3].

In summary, Hrh1 plays diverse roles in biological processes. Gene knockout models in mice and zebrafish have revealed its significance in cancer immunotherapy resistance, pancreatic cancer response to immunotherapy, and in the regulation of neurotransmitter systems and behavior. Understanding Hrh1 through these model-based studies provides insights into disease mechanisms and potential therapeutic targets, especially in cancer and neurological conditions [1,2,3].

References:

1. Li, Hongzhong, Xiao, Yi, Li, Qin, Lee, J Jack, Yu, Dihua. 2021. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. In Cancer cell, 40, 36-52.e9. doi:10.1016/j.ccell.2021.11.002. https://pubmed.ncbi.nlm.nih.gov/34822775/

2. Zhong, PingShan, Nakata, Kohei, Oyama, Koki, Kuba, Keiji, Nakamura, Masafumi. 2024. Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells. In Journal of experimental & clinical cancer research : CR, 43, 138. doi:10.1186/s13046-024-03060-5. https://pubmed.ncbi.nlm.nih.gov/38715057/

3. Yao, Yuxiao, Baronio, Diego, Chen, Yu-Chia, Jin, Congyu, Panula, Pertti. 2023. The Roles of Histamine Receptor 1 (hrh1) in Neurotransmitter System Regulation, Behavior, and Neurogenesis in Zebrafish. In Molecular neurobiology, 60, 6660-6675. doi:10.1007/s12035-023-03447-z. https://pubmed.ncbi.nlm.nih.gov/37474883/