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2022: Synthetic cannabinoids as a host-targeting approach to reduce inflammation and clear intracellular infection

Hailey Barker
University of Florida

Co-authors: Mariola J. Edelmann1
1University of Florida

Salmonella Typhimurium is a Gramnegative intracellular bacterium that causes foodborne illness, characterized by robust inflammation of the gastrointestinal tract. Salmonella infects a variety of cells, including antigen-presenting cells such as macrophages. Our laboratory discovered that host lipid metabolism is a critical process targeted by this pathogen. Specifically, Salmonella affects the host endocannabinoid (eCB) metabolism involved in the cell’s anti-inflammatory status.

Upon the highly proinflammatory infection with Salmonella that causes damage to the epithelial cells of the small intestine, there is a critical need for the host macrophage to shift from an M1 phenotype to M2. M2 phenotype is associated with resolving inflammation and improvement in tissue healing. Our study has demonstrated that eCBs and synthetic cannabinoids (CBs) prime macrophages towards a more phagocytic and less inflammatory M2 phenotype. Hence, the CBs are expected to help with bacterial clearance and reduce inflammation.

This study aimed to determine if synthetic CBs can modify innate immune responses directed against Salmonella and help maintain homeostasis during this highly inflammatory infection. Towards this goal, we infected RAW264.7 or bone marrow-derived primary macrophages (BMDMs) with S. Typhimurium, followed by exposure to such CBs as noladin ether and WIN55,212-2. The cytokine analysis was done at 2- and 24-hours post-infection, revealing that WIN55,2122 can completely block proinflammatory TNF-alpha responses. Additionally, we evaluated the effect of CBs on bacterial clearance, where WIN55,212-2 was shown to increase bacterial clearance.

Overall, our results suggest that CBs can be used to decrease inflammation and promote host pro-phagocytic functions during Salmonella infection.

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