“IMMUNOSUPPRESSIVE” CANNABINOID CB2 RECEPTORS TAKE “IMMUNOACTIVE” ROLE IN HIGH-FAT DIET EVOKED SYSTEMIC INFLAMMATORY RESPONSE

Abstract

Background

It is widely known that cannabinoid type 2 (CB2) receptor deficiency enhances inflammatory response and further symptoms in various animal models of inflammation, allergy, or cancer. As CB2 receptors are inhibitory Gi/Go G-protein coupled receptors and as major expression site of CB2 receptors are immune cells, it is no wonder that lack of CB2 receptor might lead the exacerbated inflammation.

Aims & Objectives

Number of study shows high fat diet (HFD) induce peripheral inflammation, however contribution of CB2 receptor has not been studied yet. We therefore exposed HFD to CB2 deficient mice (CB2-KOs), and evaluated the development of peripheral hypersensitivity and neuroinflammation as well as modification of splenic immune cell population.

Method

6-weeks-old male CB2-KOs and their wild-type (WT) controls are used. All animals are single housed, and exposed to either HFD (60kcal% fat, 5.24 kcal/g) or SFD (Standard fat diet, 10kcal% fat, 3.85kcal/g). At 5th week of exposure, animals are subjected to von-Frey test to evaluate the tactile sensitivity, then sacrificed to collect the sciatic nerve and dorsal root ganglia for further immunohistochemistry, and spleen for flow cytometric analysis.

Results

Surprisingly, CB2-KOs showed the significant resistance to the HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT mice, while tactile sensitivity of HFD- fed CB2-KO remained intact. In the same animals, we further found the robust upregulation of infiltrated macrophages, chemokine receptor CXCR4 expression and modified differentiation of splenic myeloid-derived suppressor cells (MDSCs) in HFD-fed WT animals, but not in either HFD-fed CB2 knockout mice or SFD-fed CB2-KO animals (Fig 1).

Discussion & Conclusion

Based on these results, we will propose that CB2 receptors might have the bipolar regulatory role to chemokine receptor-mediated inflammatory response through the modulation of splenic MDSC differentiation, which in the end might enhance or inhibit the development of neuroinflammation depending on its cause. Present results also suggests that modulation of CB2 signaling might be able to modify the physiological change lead by metabolism change (e.g. HFD exposure), however further study using other models e.g. diabetic or inflammatory model animal is required to prove this upcoming hypothesis.