Controlling Herpes Simplex Virus-Induced Ocular Inflammatory Lesions with the Lipid-Derived Mediator Resolvin E1

Abstract

Stromal keratitis (SK) is a chronic immunopathological lesion of the eye caused by herpes simplex virus-1 (HSV-1) infection and a common cause of blindness in humans. The inflammatory lesions are primarily perpetuated by neutrophils with the active participation of CD4+ T cells. Therefore, targeting these immune cell types represents a potentially valuable form of therapy to reduce the severity of disease. Resolvin E1 (RvE1), an endogenous lipid mediator, was shown to promote resolution in several inflammatory disease models. In the present report, we determined if RvE1 administration begun at different times after ocular infection of mice with HSV could influence the severity of SK lesions. Treatment with RvE1 significantly reduced the extent of angiogenesis and SK lesions that occurred. RvE1 treated mice had fewer numbers of inflammatory cells that included Th1 and Th17 cells as well as neutrophils in the cornea. The mechanisms by which RvE1 acts appear to be multiple. These included reducing the influx of neutrophils and pathogenic CD4+ T cells, increasing production of the anti-inflammatory cytokine IL-10, and inhibitory effects on the production of pro-inflammatory mediators and molecules such as IL-6, IFN-γ, IL-17, KC, VEGF-A, MMP-2 and MMP-9, that are involved in corneal neovascularization and SK pathogenesis. These findings are the first to show that RvE1 treatment could represent a novel approach to control lesion severity in a virally induced immunopathological disease.

Lipid Mediators in the Resolution of Inflammation

“…In HSV-induced ocular inflammation, RvE1 significantly reduces cornea lesions and angiogenesis as well as T cells and PMNs. These results indicate that RvE1 represents a novel approach to control virus-induced diseases (Rajasagi et al 2011). A recent study showed a phenotype of delayed wound healing in cornea of female mice.…”

Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators

“…10 These include resolvin D1 (7S, 8R, 17S-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid), resolvin D2 (7S, 16R, 17S-trihydroxy-4Z, 8E, 10Z, 12E, 14E, 19Z-DHA), 17R-HDHA (17R-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-DHA), neuroprotectin D1/NPD1 (10R, 17S-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA), resolvin E1 (5S, 12R, 18R-trihydroxy-6Z, 8E, 10E, 14Z, 16E-eicosapentaenoic acid), and most recently maresin 1 (7R, 14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-DHA). 11 In addition to confirming the original structural assignments and potent anti-inflammatory and pro-resolving actions in vivo of resolvins, lipoxins, and maresins, 10 new studies from others demonstrate their potent actions in experimental colitis, 12 arthritis, 13 arthritic pain, 14 ocular diseases, 15 resolving obesity, 16 and diabetes. 17 Importantly, synthetic SPMs permitted their identification in other biologic sources, including, for example, human inflammatory responses, 18,19 human serum, 20 fish, 21 and other marine organisms 22 and the invertebrate phyla.…”

“…Specific SPM members (eg, RvD1) also carry additional actions, such as pain regulation and control of local chemokines. [12][13][14][15] In human skin blisters (a PMN-driven response), biosynthesis of 15-epi-LXA 4 and LXA 4 and up-regulation of ALX/FPR2 (LXA 4 receptor) are key in mediating the anti-inflammatory and proresolving actions of low-dose aspirin. 19 Therefore, in the present studies, we systematically investigated LM profiles of human apoptotic PMNs and activated freshly isolated PMNs to determine their contributions, as well as PMN MPs.…”

TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions

“…The single-cell suspensions obtained from the corneas were stained for different cell surface molecules for fluorescence-activated cell sorter (FACS) analysis. To measure the number of IFN-␥-producing CD4 ϩ T cells, intracellular cytokine staining (ICS) was performed by stimulating the corneal single-cell suspensions with PMA-ionomycin or UV-inactivated HSV-1 as described previously (20). The stained samples were acquired with a FACSCalibur apparatus (BD Biosciences), and the data were analyzed using FlowJo software (Tree Star, Ashland, OR).…”

“…for the development and progression of clinical lesions by using a slit-lamp biomicroscope (Kowa Company, Nagoya, Japan). The scoring system was as follows: 0, normal cornea; ϩ1, mild corneal haze; ϩ2, moderate corneal opacity or scarring; ϩ3, severe corneal opacity but iris visible; ϩ4, opaque cornea and corneal ulcer; ϩ5, corneal rupture and necrotizing keratitis (20).…”