Δ9-Tetrahydrocannabinol Impairs the Inflammatory Response to Influenza Infection: Role of Antigen-Presenting Cells and the Cannabinoid Receptors 1 and 2

(9)-tetrahydrocannabinol ((9)-THC) has potent immune modulatory properties and can impair pathogen-induced immune defenses, which in part have been attributed to ligation of the cannabinoid receptors 1 (CB1) and 2 (CB2). Most recently, dendritic cells (DC) were identified for their potential to enhance influenza-induced immunopathology in mice lacking CB1 and CB2 ((CB1CB2/)-C-/). This study focused on the modulation of the inflammatory immune response to influenza by (9)-THC and the role of CB1 and/or CB2 as receptor targets for (9)-THC. C57Bl/6 (wild type) and (CB1CB2/)-C-/ mice were administered (9)-THC (75mg/kg) surrounding the intranasal instillation of A/PR/8/34 influenza virus. Three days post infection (dpi), (9)-THC broadly decreased expression levels of mRNA induced by the innate immune response to influenza, suppressed the percentage of interferon-gamma (IFN-)producing CD4 and interleukin-17producing NK1.1 cells, and reduced the influx of antigen-presenting cells (APC), including inflammatory myeloid cells and monocytes/macrophages, into the lung in a CB1- and/or CB2-dependent manner. (9)-THC had little effect on the expression of CD86, major histocompatibility complex I (MHC I), and MHC II by APC isolated from the lung. In vitro studies demonstrated that lipopolysaccharide (LPS)induced maturation was suppressed by (9)-THC in bone marrowderived DC (bmDC). Furthermore, antigen-specific IFN- production by CD8 T cells after coculture was reduced by (9)-THC treatment of bmDC in a CB1- and/or CB2-dependent manner. Collectively, these studies suggest that (9)-THC potently suppresses myeloid cell immune function, in a manner involving CB1 and/or CB2, thereby impairing immune responses to influenza infection.