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Contrasting approaches directing immunometabolism are investigated to mitigate FBR: a broadly suppressive metabolic inhibitor (MI) cocktail comprised of 2\u2010deoxyglucose (2\u2010DG), metformin, and 6\u2010diazo\u20105\u2010oxo\u2010l\u2010norleucine (DON) with daily systemic dosing regimen, and local weekly injection of the more narrowly focused tryptophan catabolizing IDO\u2010Gal3 fusion protein. Treatments significantly decrease FBR capsule formed around subcutaneously implanted cellulose disks. MI cocktail results in a substantially thinner FBR capsule (40% of control), while weekly local injection of IDO\u2010Gal3 also results in a thinner FBR capsule (69% of control). RNA\u2010sequencing capsule transcripts reveal MI cocktail promotes quiescence, with decreased antigen processing and presentation, T helper subset differentiation, and cytokine\u2010cytokine receptor pathway. IDO\u2010Gal3 promotes pro\u2010regenerative, alternatively activated M2\u2010like macrophages and T helper 2 cells, with increased expression of type 2 response\u2010associated genes (<jats:italic>Il4<\/jats:italic>, <jats:italic>Il13<\/jats:italic>, <jats:italic>Arg1<\/jats:italic>, <jats:italic>Mrc1<\/jats:italic>, <jats:italic>Chil3<\/jats:italic>, <jats:italic>Gata3<\/jats:italic>). IDO\u2010Gal3 decreases pro\u2010inflammatory innate sensing pathways, and C\u2010type lectin receptor, NOD\u2010like receptor, RIG\u2010I\u2010like receptor, and Toll\u2010like receptor signaling. This work helps define key gene targets and pathways concomitantly regulated in the FBR capsule during immunometabolic modulation compared to control FBR capsule.<\/jats:p>","DOI":"10.1002\/adhm.202400602","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T23:55:52Z","timestamp":1723766152000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Immunometabolic Approaches Mitigating Foreign Body Response and Transcriptome Characterization of the Foreign Body Capsule"],"prefix":"10.1002","volume":"14","author":[{"given":"Sabrina L.","family":"Macias","sequence":"first","affiliation":[{"name":"J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida  Gainesville FL 32611 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Palmer","sequence":"additional","affiliation":[{"name":"J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida  Gainesville FL 32611 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer A.","family":"Simonovich","sequence":"additional","affiliation":[{"name":"J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida  Gainesville FL 32611 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan A.","family":"Clark","sequence":"additional","affiliation":[{"name":"J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida  Gainesville FL 32611 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory A.","family":"Hudalla","sequence":"additional","affiliation":[{"name":"J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida  Gainesville FL 32611 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6474-7769","authenticated-orcid":false,"given":"Benjamin G.","family":"Keselowsky","sequence":"additional","affiliation":[{"name":"J. 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