Genetic deletion of the cannabinoid receptors CB1 and CB2 enhances inflammation with diverging effects on skin wound healing in mice

Aims: Inflammation during wound healing is both essential and critical for restoring tissue integrity. Participating cells secrete soluble factors to regulate the inflammatory phase and to induce the adjacent regenerative processes. If pro-inflammatory signals are overexpressed, the wound stagnates in the inflammatory phase, which decelerates regular wound healing. The endocannabinoid system is ascribed great significance in maintenance of tissue homeostasis. It mediates several effects through the cannabinoid receptors CB1 and CB2. Main methods: In order to clarify the role of these receptors in wound healing, excisional wounds were created on wildtype and CB1 and CB2 knockout mice. The wound closure was analyzed over a period of 14 days, and cytokine concentrations of tissue homogenisates were measured by ELISA. MSCs were isolated from the animals' subcutaneous adipose tissue and analyzed for viability and differentiation capacity, in vitro. Key findings: Deletion of CB2 increased Interleukin (IL)-6 and tumor necrosis factor (TNF)-α but did not affect tissue regeneration. In CB1-deficient animals, wound closure was delayed during early phases of healing, which was accompanied by increased concentrations of monocyte chemoattractant protein (MCP)-1 and TNF-α. CB1 and CB2 knockout MSCs presented altered viability and differentiation capacity compared to wildtype MSCs. The CB1-deficient MSCs released high levels of MCP-1 upon stimulation with TNF-α and IL-1β. Significance: The data indicate that both cannabinoid receptors regulate inflammation, and this study emphasizes the important role of CB1 in wound repair. Furthermore, our findings suggest that the secretome of CB1-deficient MSCs may contribute to the wound healing delay, in vivo.