Δ9-Tetrahydrocannabinol exposure shifts eosinophil and macrophage transcriptional programs towards an anti-inflammatory phenotype in helminth infection

Abstract Cannabis use is increasing globally, yet the immunological effects of Δ9-tetrahydrocannabinol (THC), 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 THC exposure alters immune responses to the helminth Nippostrongylus brasiliensis (Nb), which infects the lung and small intestine of mice. C57BL/6J mice were treated with THC (5 mg/kg/day) or vehicle for 14 days prior to helminth infection and assessed for parasite burden, innate immune cell and T cell responses, and transcriptional changes in lung eosinophils and macrophages. THC exposure did not significantly alter infection-associated weight loss or helminth burden; however, THC 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 THC-treated infected mice. Bulk RNA sequencing showed that THC 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, THC 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 THC mitigated infection-associated loss of lung collagen. Collectively, these findings indicate that THC reshapes the immune response to helminth infection by restraining innate and T cell effector responses while altering lung eosinophil and macrophage activation programs.