title: Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2.
abstract: 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) and/or CB(2) as receptor targets for Δ(9)-THC. C57Bl/6 (wild type) and CB(1) (-/-)CB(2) (-/-) mice were administered Δ(9)-THC (75 mg/kg) surrounding the intranasal instillation of A/PR/8/34 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 monocytes/macrophages, into the lung in a CB(1)- and/or 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)- and/or CB(2)-dependent manner. Collectively, these studies suggest that Δ(9)-THC potently suppresses myeloid cell immune function, in a manner involving CB(1) and/or CB(2), thereby impairing immune responses to influenza infection.
authors.affiliation: Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824, USA. kamins11@msu.edu
authors.forename: Peer W F
authors.initials: PW
authors.lastname: Karmaus
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Crawford
authors.forename: Barbara L F
authors.initials: BL
authors.lastname: Kaplan
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018920:Coculture Techniques; D013759:Dronabinol / Q000633:toxicity*; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000502:physiology*
chemical_list: D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol