IL-17 has been associated with selected inflammatory and autoimmune diseases. We characterized the expression of this proinflammatory cytokine following HSV-1 corneal infection and investigated whether IL-17R signaling modulated the host response to the viral pathogen at early time-points postinfection. IL-17 was elevated in the murine cornea 24 h after high-dose virus infection and subsequently persisted at low levels during the first week. Immunofluorescent studies showed that the IL-17R was expressed by cultured mouse corneal fibroblasts. Exposure of corneal cells to IL-17 led to production of IL-6 and MIP-2 in vitro and in vivo, indicating that the IL-17R was functional. Mice lacking IL-17R displayed significantly reduced neutrophil infiltration and corneal opacity. However, this effect was transient, as corneal pathology and neutrophil influx resembled that of wild-type (WT) hosts 4 days postinfection. HSV-1 growth and clearance in IL-17R(-/-) hosts were similar to that of the WT controls. Infection of IFN-gamma gene knockout mice was associated with elevated IL-17 levels and accelerated corneal opacity, suggesting that IFN-gamma negatively regulated IL-17 expression. Collectively, our results establish that IL-17 is rapidly produced in the cornea after HSV-1 infection and is regulated at least in part by IFN-gamma. The absence of IL-17 signaling results in a transient decrease in the expression of proinflammatory mediators, neutrophil migration, and corneal pathology, but control of virus growth in the cornea and trigeminal ganglia is not compromised. Thus, IL-17 actively influences early virus-induced corneal inflammation.
Analogous to CD4+ T cells, neutrophils are essential participants in delayed-type hypersensitivity (DTH) to Herpes simplex virus type 1 antigen. However, what role they play in this cellular immune response is unclear. The recent recognition that neutrophils are potent producers of chemokines led us to hypothesize that they may help recruit CD4+ effector T cells. In the present study, we show that neutrophil depletion was accompanied by a marked decrease in the numbers of CD4+ and CXC receptor 3+ (CXCR3+)-expressing cells migrating to the DTH site and a sharp drop in the levels of interferon-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig). Purified mouse neutrophils were stimulated directly by IFN-gamma to secrete these chemokines, and neutrophils at the DTH site expressed IP-10. IFN-gamma knockout mice, which manifested depressed ear-swelling following DTH challenge, made little IP-10 and no Mig. Reconstitution of these mice with IFN-gamma induced CXCR3 ligand synthesis. Depletion of neutrophils or CD4+ T cells but not CD8+ T cells markedly reduced IFN-gamma levels, suggesting the former were direct (or indirect) cellular sources of this cytokine. Collectively, our results support the hypothesis that neutrophil production of T cell-recruiting chemokines contributes to the regulation and amplification of the DTH response.
Sensitized CD4+ T cells play an essential role in delayed type hypersensitivity (DTH) elicited by HSV-1 antigen. As activated CD4+ T cells express CXCR3, we investigated whether this chemokine receptor was involved in their recruitment. Antibody blockade of CXCR3 suppressed DTH, whereas ear pinna swelling was not impaired in mice lacking the gene for CCR5, another frequently expressed chemokine receptor. CXCR3 ligands IP-10 and Mig were elevated at the DTH site. Their neutralization significantly reduced DTH ear swelling and CD4+ T cell influx. Furthermore, CXCR3 ligand expression was abrogated and DTH diminished in mice unable to make IFN-gamma, a potent inducer of IP-10 and Mig. Interestingly, neutralization of CXCR3 or its ligands did not compromise host resistance to virus replication. Collectively, these results suggest that in the sensitized host, CXCR3, IP-10, and Mig are required for optimal DTH responsiveness but are not essential for containing HSV-1 replication in the ear pinna.
In this study we show that murine and human neutrophils are capable of secreting IP-10 in response to communication from the HSV-1 infected cornea and that they do so in a time frame associated with the recruitment of CD8+T cells and CXCR3-expressing cells. Cellular markers were used to establish that neutrophil influx corresponded in time to peak IP-10 production, and cellular depletion confirmed neutrophils to be a significant source of IP-10 during HSV-1 corneal infection in mice. A novelex vivomodel for human corneal tissue infection with HSV-1 was used to confirm that cells resident in the cornea are also capable of stimulating neutrophils to secrete IP-10. Our results support the hypothesis that neutrophils play a key role in T-cell recruitment and control of viral replication during HSV-1 corneal infection through the production of the T-cell recruiting chemokine IP-10.
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