title: Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection.
abstract: We and others have reported that simultaneous targeted deletion of CB(1) and CB(2) resulted in exacerbation of immune reactivity, suggesting a role of endocannabinoids in down-regulating immune function. In this study, we demonstrate that APC function is enhanced specifically in the absence of CB(1) and CB(2) signaling, resulting in an exacerbated immune response phenotype. After influenza infection, CB(1)(-/-)CB(2)(-/-) mice showed more pronounced pulmonary damage, increased inflammatory cell infiltrate, inflammation, and a greater cellular immune responses compared with WT mice, as evidenced by transcriptome analysis, more robust T cell activation, and effector cell cytokine production. After direct activation in vitro, there were no differences in the percentages of cytokine-producing CD4(+) T cells between CB(1)(-/-)CB(2)(-/-) and WT mice. However, untreated CB(1)(-/-)CB(2)(-/-) mice routinely had fewer naïve T cells compared with WT, suggesting dysregulation of APC immune homeostasis. Moreover, bmDCs and AM isolated from CB(1)(-/-)CB(2)(-/-) mice exhibited a more mature phenotype, with and without TLR stimulation, and bmDCs elicited T cells more robustly than WT mice. Collectively, these findings implicate a role for CB(1) and CB(2) on APCs in regulating immune responses and immune homeostasis.
authors.affiliation: Cell and Molecular Biology Program, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Peer W F
authors.initials: PW
authors.lastname: Karmaus
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
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; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D017353:Gene Deletion; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2