Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection role of antigen-presenting cells and the cannabinoid receptors 1 and 2.
Δ(9)-tetrahydrocannabinol (Δ(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 (CB(1)) and 2 (CB(2)). Most recently, dendritic cells (DC) were identified for their potential to enhance influenza-induced immunopathology in mice lacking CB(1) and CB(2) (CB(1) (--)CB(2) (--)). This study focused on the modulation of the inflammatory immune response to influenza by Δ(9)-THC and the role of CB(1) andor CB(2) as receptor targets for Δ(9)-THC. C57Bl6 (wild type) and CB(1) (--)CB(2) (--) mice were administered Δ(9)-THC (75 mgkg) surrounding the intranasal instillation of APR834 influenza virus. Three days post infection (dpi), Δ(9)-THC broadly decreased expression levels of mRNA induced by the innate immune response to influenza, suppressed the percentage of interferon-gamma (IFN-γ)-producing CD4() and interleukin-17-producing NK1.1() cells, and reduced the influx of antigen-presenting cells (APC), including inflammatory myeloid cells and monocytesmacrophages, into the lung in a CB(1)- andor CB(2)-dependent manner. Δ(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 Δ(9)-THC in bone marrow-derived DC (bmDC). Furthermore, antigen-specific IFN-γ production by CD8() T cells after coculture was reduced by Δ(9)-THC treatment of bmDC in a CB(1)- andor CB(2)-dependent manner. Collectively, these studies suggest that Δ(9)-THC potently suppresses myeloid cell immune function, in a manner involving CB(1) andor CB(2), thereby impairing immune responses to influenza infection.