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


METHODS
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).


RESULTS
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.


CONCLUSIONS
Our novel findings demonstrate that NPD1 treatment could represent a valuable therapeutic approach to control SK lesions.
Biomedical & Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee.
Naveen K
NK
Rajasagi
Pradeep B J
PB
Reddy
Sachin
S
Mulik
Per
P
Gjorstrup
Barry T
BT
Rouse
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016510:Corneal Neovascularization / Q000188:drug therapy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D016849:Keratitis, Herpetic / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; C487679:protectin D1; D004281:Docosahexaenoic Acids
HSV-1; NPD1; herpes stromal keratitis; immunopathology