Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology

• Published in: Investigative ophthalmology & visual science 2013-09, Vol.54 (9), p.6269-6279
• Main Authors: Rajasagi, Naveen K, Reddy, Pradeep B J, Mulik, Sachin, Gjorstrup, Per, Rouse, Barry T
• Format: Article
• Language: English
• Subjects: Administration, Topical; Animals; Anti-Inflammatory Agents - therapeutic use; Biomarkers - metabolism; CD4-Positive T-Lymphocytes - metabolism; Chemokines - metabolism; Corneal Neovascularization - drug therapy; Cytokines - metabolism; Disease Models, Animal; Docosahexaenoic Acids - therapeutic use; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Immunohistochemistry; Keratitis, Herpetic - drug therapy; Keratitis, Herpetic - immunology; Mice; Mice, Inbred C57BL; Neutrophils - metabolism
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.13-12152

Neuroprotectin D1 (NPD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3-polyunsaturated fatty acid docosahexaenoic acid (DHA). The purpose of this study is to test the therapeutic potential of NPD1 for the treatment of herpes simplex virus (HSV)-induced stromal keratitis (SK) using a mouse model. C57BL/6 mice were infected ocularly with HSV-1 strain RE. Infected animals were treated topically with methyl ester prodrug NPD1 (300 ng/eye, 5-μL drop). Development of SK lesions, infiltration of inflammatory cells into the cornea, and production of proinflammatory cytokines, chemokines, and angiogenic factors were compared to untreated animals using slit-lamp biomicroscopy, flow cytometry, ELISA, and quantitative PCR (qPCR). Topical administration of NPD1 resulted in a significant reduction in the severity and incidence of SK, as well as the extent of corneal neovascularization in the NPD1-treated animals compared to their untreated counterparts. Infiltration of fewer neutrophils and pathogenic CD4⁺ T cells into the cornea, along with a lower number of cells that could be induced ex vivo to produce IFN-γ and IL-17, occurred with NPD1 treatment. Additionally, treatment with NPD1 diminished the production of proinflammatory cytokines, chemokines, and angiogenic factors, such as IL-6, CXCL1, CXCL-10, CCL-20, VEGF-A, MMP-2, and MMP-9 in the corneas of infected animals. Importantly, treatment with NPD1 increased the production of the anti-inflammatory cytokine, IL-10. Our novel findings demonstrate that NPD1 treatment could represent a valuable therapeutic approach to control SK lesions.