Ccl3, also known as macrophage inflammatory protein-1α (MIP-1α), is an important chemokine. It plays a key role in immune cell trafficking regulation and immune landscape formulation within the tumor microenvironment, and is implicated in both immune surveillance and tolerance [2]. Ccl3 exerts context-dependent antitumor and pro-tumor behaviors, and is involved in multiple signaling cascades.

In breast cancer, Ccl3-knockout transgenic allograft mouse models demonstrated that Ccl3 induced by docetaxel (DTX) was indispensable for DTX's chemotherapeutic efficacy. Ccl3 promoted pro-inflammatory macrophage polarization, facilitating phagocytosis of breast cancer cells and cancer stem cells, thus enhancing DTX chemosensitivity [1]. In silicosis, the unique Ccl3+ neutrophil population was related to the pro-fibrotic process, and administration of the Ccl3 receptor antagonist BX471 alleviated silica-induced lung fibrosis [3]. In aged mice, in vivo Ccl3 deletion rescued age-related phenotypes such as bone loss, bone marrow adiposity, and imbalanced bone marrow stromal cell (BMSC) differentiation [4]. In intervertebral disc degeneration, over-expression of Yap1 inhibited CCL3 transcription, reversing the cartilage endplate remodeling induced by lumbar instability [5].

In conclusion, Ccl3 is a crucial chemokine involved in various biological processes and disease conditions. Gene-knockout mouse models have been instrumental in revealing its functions, especially in diseases like breast cancer, silicosis, age-related bone changes, and intervertebral disc degeneration. Understanding Ccl3's role provides potential therapeutic targets for these diseases.

References:

1. Sheng, Dandan, Ma, Wei, Zhang, Rui, Liu, Tong, Liu, Suling. . Ccl3 enhances docetaxel chemosensitivity in breast cancer by triggering proinflammatory macrophage polarization. In Journal for immunotherapy of cancer, 10, . doi:10.1136/jitc-2021-003793. https://pubmed.ncbi.nlm.nih.gov/35613826/

2. Ntanasis-Stathopoulos, Ioannis, Fotiou, Despoina, Terpos, Evangelos. . CCL3 Signaling in the Tumor Microenvironment. In Advances in experimental medicine and biology, 1231, 13-21. doi:10.1007/978-3-030-36667-4_2. https://pubmed.ncbi.nlm.nih.gov/32060842/

3. Cheng, Demin, Lian, Wenxiu, Wang, Ting, Liu, Yi, Ni, Chunhui. 2024. The interplay of Cxcl10+/Mmp14+ monocytes and Ccl3+ neutrophils proactively mediates silica-induced pulmonary fibrosis. In Journal of hazardous materials, 467, 133713. doi:10.1016/j.jhazmat.2024.133713. https://pubmed.ncbi.nlm.nih.gov/38335607/

4. Yu, Degang, Zhang, Shuhong, Ma, Chao, Liu, Guangwang, Zhai, Zanjing. 2023. CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice. In JCI insight, 8, . doi:10.1172/jci.insight.159107. https://pubmed.ncbi.nlm.nih.gov/36378535/

5. Li, Hanwen, Tang, Yingchuang, Liu, Zixiang, Li, Bin, Chen, Hao. 2024. Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling. In Bone research, 12, 34. doi:10.1038/s41413-024-00331-x. https://pubmed.ncbi.nlm.nih.gov/38816384/