Abstract
Cannabis use is increasing globally, yet the immunological effects of Δ9-tetrahydrocannabinol, the main intoxicating component of cannabis, remain incompletely understood. Given prior evidence that endocannabinoid signaling influences helminth immunity and type 2 inflammation, we investigated how sustained Δ9-tetrahydrocannabinol exposure alters immune responses to the helminth Nippostrongylus brasiliensis, which infects the lung and small intestine of mice. C57BL/6J mice were treated with Δ9-tetrahydrocannabinol (5 mg/kg/d) or vehicle for 14 d prior to helminth infection and assessed for parasite burden, innate immune cell and T cell responses, and transcriptional changes in lung eosinophils and macrophages. Δ9-Tetrahydrocannabinol exposure did not significantly alter infection-associated weight loss or helminth burden; however, Δ9-tetrahydrocannabinol selectively restrained infection-induced circulating eosinophils and monocytes while increasing regulatory T cells. T cell activation assays showed reduced TNFα and IFNγ secretion in splenocytes from Δ9-tetrahydrocannabinol-treated infected mice. Bulk RNA sequencing showed that Δ9-tetrahydrocannabinol shifted lung eosinophils and CD11c+ lung macrophage-enriched cells from inflammatory, fibrotic, and costimulatory pathways toward stress and metabolic-adaptive transcriptional programs. Within the infected macrophage-enriched population, Δ9-tetrahydrocannabinol reduced CD80 expression while increasing MHC class II and antigen presentation-associated genes, suggesting a potential shift in macrophage-mediated T cell activation. Consistent with altered inflammatory and tissue remodeling-associated programs, immunofluorescent staining showed that Δ9-tetrahydrocannabinol mitigated infection-associated loss of lung collagen. Collectively, these findings indicate that Δ9-tetrahydrocannabinol reshapes the immune response to helminth infection by restraining innate and T cell effector responses while altering lung eosinophil and macrophage activation programs.
Authors
Jennett J, Olmos M, Lam KM, Midou S, DiPatrizio NV, Nair MG