{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T04:05:39Z","timestamp":1770696339088,"version":"3.49.0"},"reference-count":29,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870695"],"award-info":[{"award-number":["81870695"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974288"],"award-info":[{"award-number":["81974288"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20241725"],"award-info":[{"award-number":["BK20241725"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008832","name":"Nanjing Science and Technology Development Plan","doi-asserted-by":"publisher","award":["YKK21095"],"award-info":[{"award-number":["YKK21095"]}],"id":[{"id":"10.13039\/501100008832","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1), is a major cause of infectious blindness. Macrophages are key antiviral effector cells, yet the metabolic mechanisms driving their protective responses remain poorly defined. This study aimed to determine whether interleukin-33 (IL-33) modulates macrophage metabolism and function to enhance antiviral protection in HSK. Methods: Bone marrow-derived macrophages (BMDMs) were stimulated with IL-33, followed by phenotypic and functional characterization using qRT-PCR, flow cytometry, and immunofluorescence. Integrated transcriptomic and non-targeted LC-MS metabolomic profiling was performed to uncover regulatory pathways. For in vivo validation, differently treated BMDMs were adoptively transferred subconjunctivally into a mouse HSK model. Clinical scoring, fluorescein staining, TCID50 quantification of tear samples, and corneal viral gene detection were used to evaluate disease severity and viral burden. Results: IL-33 stimulation increased CD169 and MHC-II expression, expanded the CD169+ macrophage subset, and suppressed HSV-1 replication in vitro. Multi-omics integration identified 616 differentially expressed genes and 417 differentially expressed metabolites, revealing substantial remodeling of lipid and amino acid metabolism and suggesting a critical IL-33\u2013lipoprotein lipase (LPL)\u2013palmitoylcarnitine (L-PC) metabolic axis. In vivo, prophylactic adoptive transfer of IL-33-treated BMDMs significantly reduced corneal opacity, epithelial injury, tear viral titers, and virogene expression. LPL inhibition eliminated these benefits, whereas L-PC supplementation partially restored antiviral and clinical improvements. Conclusions: IL-33 reprograms macrophages toward a CD169+ antiviral phenotype through an LPL-dependent metabolic pathway, establishing an LPL\u2013L-PC axis essential for enhanced antiviral function and protection against HSK. These findings highlight metabolic tuning of macrophages as a potential preventive immunomodulatory approach for HSV-1-induced ocular disease.<\/jats:p>","DOI":"10.3390\/ph19020285","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IL-33-Driven Macrophage Reprogramming as a Potential Immunometabolic Strategy for Herpes Simplex Keratitis"],"prefix":"10.3390","volume":"19","author":[{"given":"Yun","family":"He","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"},{"name":"Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaoyao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junwen","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenchen","family":"Wang","sequence":"additional","affiliation":[{"name":"The Eye Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junpeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changyu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/s41587-020-00781-8","article-title":"Targeting herpes simplex virus with CRISPR-Cas9 cures herpetic stromal keratitis in mice","volume":"39","author":"Yin","year":"2021","journal-title":"Nat. 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