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Given prior evidence that endocannabinoid signaling influences helminth immunity and type 2 inflammation, we investigated how sustained \u03949-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 \u03949-tetrahydrocannabinol (5\u2005mg\/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. \u03949-Tetrahydrocannabinol exposure did not significantly alter infection-associated weight loss or helminth burden; however, \u03949-tetrahydrocannabinol selectively restrained infection-induced circulating eosinophils and monocytes while increasing regulatory T cells. T cell activation assays showed reduced TNF\u03b1 and IFN\u03b3 secretion in splenocytes from \u03949-tetrahydrocannabinol-treated infected mice. Bulk RNA sequencing showed that \u03949-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, \u03949-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 \u03949-tetrahydrocannabinol mitigated infection-associated loss of lung collagen. Collectively, these findings indicate that \u03949-tetrahydrocannabinol reshapes the immune response to helminth infection by restraining innate and T cell effector responses while altering lung eosinophil and macrophage activation programs.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag131","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:39:07Z","timestamp":1790275147000},"source":"Crossref","is-referenced-by-count":0,"title":["\u03949-Tetrahydrocannabinol exposure shifts eosinophil and macrophage transcriptional programs toward an anti-inflammatory phenotype in helminth infection"],"prefix":"10.1093","volume":"118","author":[{"given":"Jennell","family":"Jennett","sequence":"first","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside , 900 University Avenue, Riverside, CA 92521, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9325-9524","authenticated-orcid":false,"given":"Martin","family":"Olmos","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside , 900 University Avenue, Riverside, CA 92521, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7469-1818","authenticated-orcid":false,"given":"Ka Man","family":"Lam","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside , 900 University Avenue, Riverside, CA 92521, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3724-7812","authenticated-orcid":false,"given":"Sarah","family":"Midou","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside , 900 University Avenue, Riverside, CA 92521, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas V","family":"DiPatrizio","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside , 900 University Avenue, Riverside, CA 92521, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-5161","authenticated-orcid":false,"given":"Meera G","family":"Nair","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, School of Medicine, University of California Riverside , 900 University Avenue, Riverside, CA 92521, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"2026101005120085700_qiag131-B1","author":"Substance Abuse and Mental Health Services Administration"},{"key":"2026101005120085700_qiag131-B2","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1124\/pr.54.2.161","article-title":"International Union of Pharmacology. 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