Nmur1-KO Mouse

Neuromedin U receptor 1 (NMUR1), also known as Nmur1, is a G-protein-coupled receptor (GPCR) that plays a crucial role in various physiological processes, including immune response, bone remodeling, and inflammation. NMUR1 is expressed in several cell types, including eosinophils, mast cells, and innate lymphoid cells (ILCs), and is activated by its ligand, neuromedin U (NMU).

Research has shown that NMUR1 expression in eosinophils is programmed by the local microenvironment and is further enhanced by inflammation. Activation of NMUR1-expressing eosinophils by NMU promotes goblet cell differentiation, thereby regulating epithelial cell differentiation and barrier immunity in the small intestine. This highlights the importance of neuroimmune-epithelial cross-talk in maintaining tissue homeostasis [1].

NMUR1 is also involved in bone remodeling. Knockdown of Nmur1 in MC3T3-E1 cells in vitro revealed specific cell signaling events, such as mTOR phosphorylation, that are deficient in the absence of NMUR1 expression. However, global knockout of Nmur1 in vivo did not affect trabecular bone volume in femora and tibiae, suggesting that NMUR1 is required for NMU-dependent signaling in MC3T3-E1 cells, but it is not required for the NMU-mediated effects on bone remodeling in vivo [2].

NMUR1 signaling promotes inflammatory ILC2 responses. The neuropeptide NMU activates ILC2s through NMUR1, resulting in immediate and strong production of innate inflammatory and tissue repair cytokines. This NMU-NMUR1 signaling pathway is crucial for the rapid activation of ILC2s in allergic inflammation at mucosal surfaces [3].

In obese osteoarthritis patients, NMUR1 expression is significantly elevated in mast cells in the synovial membrane. This suggests that NMUR1 may be involved in the pathogenesis of obesity-related disorders and osteoarthritis [4].

NMUR1 is also involved in the rapid activation of airway ILC2s in mild asthma. After allergen challenge, sputum ILC2s expressing NMUR1 are significantly increased, and NMUR1+ ILC2s express IL-5/IL-13. NMU treatment stimulates T2 cytokine expression by ILC2s, indicating that the NMU/NMUR1 axis is an important early activator of ILC2s in eosinophilic inflammatory responses in asthma [5].

Neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection. NMU expression levels increase in inflamed intestinal tissues from both mice and humans, and NMU induces AREG production in mouse and human ILC2s. This indicates that NMU-NMUR1 signaling promotes non-redundant functions of ILC2s in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation [6].

In conclusion, NMUR1 is a key regulator of immune response, bone remodeling, and inflammation. It is involved in the regulation of eosinophil activity, goblet cell differentiation, and barrier immunity in the small intestine. NMUR1 also plays a role in bone remodeling, as it is required for NMU-dependent signaling in MC3T3-E1 cells. Additionally, NMUR1 signaling promotes inflammatory ILC2 responses, highlighting its importance in allergic inflammation at mucosal surfaces. Further research is needed to fully understand the role of NMUR1 in various physiological processes and diseases.

References:

1. Li, Yu, Liu, Shaorui, Zhou, Kewen, He, Danyang, Xu, Heping. 2023. Neuromedin U programs eosinophils to promote mucosal immunity of the small intestine. In Science (New York, N.Y.), 381, 1189-1196. doi:10.1126/science.ade4177. https://pubmed.ncbi.nlm.nih.gov/37708282/

2. Hsiao, Yu-Tin, Manikowski, Kelli J, Snyder, Samantha, Allen, Matthew R, Lowery, Jonathan W. 2021. NMUR1 in the NMU-Mediated Regulation of Bone Remodeling. In Life (Basel, Switzerland), 11, . doi:10.3390/life11101028. https://pubmed.ncbi.nlm.nih.gov/34685399/

3. Wallrapp, Antonia, Riesenfeld, Samantha J, Burkett, Patrick R, Regev, Aviv, Kuchroo, Vijay K. 2017. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. In Nature, 549, 351-356. doi:10.1038/nature24029. https://pubmed.ncbi.nlm.nih.gov/28902842/

4. Tsukada, Ayumi, Takata, Ken, Takano, Shotaro, Takaso, Masashi, Uchida, Kentaro. 2022. Increased NMUR1 Expression in Mast Cells in the Synovial Membrane of Obese Osteoarthritis Patients. In International journal of molecular sciences, 23, . doi:10.3390/ijms231911237. https://pubmed.ncbi.nlm.nih.gov/36232539/

5. Ju, Xiaotian, Nagashima, Akimichi, Dvorkin-Gheva, Anna, Gauvreau, Gail M, Sehmi, Roma. . Neuromedin-U Mediates Rapid Activation of Airway Group 2 Innate Lymphoid Cells in Mild Asthma. In American journal of respiratory and critical care medicine, 210, 755-765. doi:10.1164/rccm.202311-2164OC. https://pubmed.ncbi.nlm.nih.gov/38598774/

6. Tsou, Amy M, Yano, Hiroshi, Parkhurst, Christopher N, Lira, Sergio A, Artis, David. 2022. Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces. In Nature, 611, 787-793. doi:10.1038/s41586-022-05297-6. https://pubmed.ncbi.nlm.nih.gov/36323781/