Ccl4, also known as macrophage inflammatory protein (MIP)-1β, is a CC chemokine. It interacts with its specific receptor CCR5, collaborating with related CC chemokines like CCL3 and CCL5 that can also bind CCR5. Ccl4 has diverse effects on immune and non-immune cells, playing roles in various biological processes such as inflammation and cell-cell communication [1].

In multiple disease conditions, Ccl4 shows distinct functions. In the tumor microenvironment, it can promote tumor development by recruiting regulatory T cells and pro-tumorigenic macrophages, yet under some circumstances, it can enhance tumor immunity [1]. In aging-related vascular dysfunction, Ccl4 contributes to angiogenic insufficiency via activating oxidative stress and endothelial inflammation, and Ccl4 knockout mice exhibit vascular and dermal anti-aging effects [2]. In eosinophilic airway inflammation, epithelial cell-derived Ccl4 is involved in eosinophil accumulation and activation, and administration of a Ccl4-neutralizing antibody attenuates eosinophilic airway infiltration in a mouse model [3,7]. In osteoarthritis, Ccl4 upregulation is associated with chondrocyte apoptosis and ROS levels, and the CCR5 inhibitor maraviroc mitigates these effects in chondrocytes [4]. In osteosarcoma, Ccl4 promotes cell migration through the mir-3927-3p/Integrin αvβ3 axis [5]. In the neurovascular endothelium, Ccl4 can modify blood-brain barrier function by inducing inflammatory signalling and barrier disruption [6].

In conclusion, Ccl4 is a multifunctional chemokine with diverse roles in various biological processes and diseases. Studies using gene knockout or inhibitor-based models in mice have revealed its significance in tumor development, aging-related vascular dysfunction, eosinophilic airway inflammation, osteoarthritis, osteosarcoma, and neuroinflammatory conditions, providing potential therapeutic targets for these diseases.