Il34, or interleukin-34, is a cytokine that activates the CSF-1 receptor (CSF-1R) along with colony-stimulating factor-1 (CSF-1). It plays crucial roles in development and innate immunity by regulating the development of multiple cell types such as tissue macrophages, osteoclasts, Langerhans cells, Paneth cells, and brain microglia. It is also involved in the differentiation of neural progenitor cells and functions in the female reproductive tract [1].

In gene knockout studies, deleting Il34 in mouse models led to significant findings. In skeletal muscle, inactivation of Il34 sustained satellite cell (SC) expansion at the cost of differentiation, causing muscle regeneration defects. In mdx mice, deleting Il34 ameliorated dystrophic muscles, indicating its role in muscle homeostasis and Duchenne muscular dystrophy [2]. In the context of cancer, p53 loss led to Il34 secretion by cancer stem cells in liver cancer. Il34 induced M2-like polarization of tumor-associated macrophages, promoting tumor immune escape. Blocking the Il34-CD36 axis elicited antitumor immunity [3]. In hepatocellular carcinoma, IL34+ cancer-associated fibroblasts promoted tumor growth and metastasis by facilitating Tregs infiltration and suppressing CD8+ T cell toxicity [4]. In myocardial ischemic/reperfusion injury, Il34 knockout mitigated cardiac remodeling, dysfunction, and fibrosis, as Il34 activated the NF-κB pathway, leading to increased CCL2 expression, macrophage recruitment, and polarization [5].

In conclusion, Il34 is essential in multiple biological processes including muscle regeneration, immune regulation in cancer, and cardiac response to injury. Gene knockout mouse models have been instrumental in revealing its role in diseases such as Duchenne muscular dystrophy, liver cancer, hepatocellular carcinoma, and myocardial ischemic/reperfusion injury, providing potential therapeutic targets for these conditions.

References:

1. Stanley, E Richard, Chitu, Violeta. 2014. CSF-1 receptor signaling in myeloid cells. In Cold Spring Harbor perspectives in biology, 6, . doi:10.1101/cshperspect.a021857. https://pubmed.ncbi.nlm.nih.gov/24890514/

2. Su, Yang, Cao, Yuxin, Liu, Chang, Zhang, Zeyu, Meng, Qingyong. 2023. Inactivating IL34 promotes regenerating muscle stem cell expansion and attenuates Duchenne muscular dystrophy in mouse models. In Theranostics, 13, 2588-2604. doi:10.7150/thno.83817. https://pubmed.ncbi.nlm.nih.gov/37215564/

3. Nian, Zhigang, Dou, Yingchao, Shen, Yiqing, Tian, Zhigang, Wei, Haiming. 2024. Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation. In Immunity, 57, 2344-2361.e7. doi:10.1016/j.immuni.2024.08.015. https://pubmed.ncbi.nlm.nih.gov/39321806/

4. Wang, Ganggang, Zhou, Zhijie, Jin, Wenzhi, Zhang, Hao, Wang, Xiaoliang. 2023. Single-cell transcriptome sequencing reveals spatial distribution of IL34+ cancer-associated fibroblasts in hepatocellular carcinoma tumor microenvironment. In NPJ precision oncology, 7, 133. doi:10.1038/s41698-023-00483-9. https://pubmed.ncbi.nlm.nih.gov/38081923/

5. Zhuang, Lingfang, Zong, Xiao, Yang, Qian, Fan, Qin, Tao, Rong. 2023. Interleukin-34-NF-κB signaling aggravates myocardial ischemic/reperfusion injury by facilitating macrophage recruitment and polarization. In EBioMedicine, 95, 104744. doi:10.1016/j.ebiom.2023.104744. https://pubmed.ncbi.nlm.nih.gov/37556943/