Cannabinoid CB2 receptors enhance high-fat diet evoked peripheral neuroinflammation

It is known that the cannabinoid type 2 (CB2) receptor has an anti-inflammatory role. Therefore, animals without CB2 receptors show enhanced inflammation and pain in the model of chronic pain, e.g., neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanisms of pain exacerbation in nerve-injured CB2 knockouts, as they displayed robust upregulation of leptin receptors and leptin signaling in the peripheral nerve. Due to these past results, we hypothesized that CB2 receptor deficiency might also modify the peripheral neuroinflammation led by chronic exposure to a high-fat diet (HFD). Interestingly, CB2 knockout animals showed significant resistance to HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT animals, while tactile sensitivity of HFD-fed CB2 knockouts remained intact. HFD-fed WT animals also displayed the robust upregulation of chemokine CXCR4 expression with increased macrophage infiltration, which was never observed in HFD-fed CB2 knockout mice. Moreover, 5-week HFD exposure led significant increase of CD11b⁺Ly6G^-Ly6C^high cells and a decrease of CD11b⁺Ly6G⁺Ly6C^low cells in the spleen of WT animals, which was also not found in either HFD-fed CB2 knockouts or standard diet-fed WT and CB2 animals. Together with past reports, these results suggest that CB2 receptors might have a double-sided regulatory role in the context of inflammation development or, more widely, immune system regulation. We propose that CB2 signaling is not always anti-inflammatory and could take a pro-inflammatory role depending on the cause of the inflammation.