Herpes Stromal Keratitis: Erosion of Ocular Immune Privilege by Herpes Simplex Virus

Jared E Knickelbein; Kristine-Ann Buela; Robert L Hendricks


Future Virology. 2010;5(6):699-708. 

In This Article

Cytokines & Chemokines in HSK

Ideally, cytokines coordinate inflammatory responses to eliminate pathogens with minimal injury to host tissue. Indeed, the cytokines that orchestrate the innate immune response that clears HSV-1 from the infected cornea appear to accomplish this goal, as the virus is cleared with no apparent permanent damage to the cornea. In mice that are deficient in CD4 T cells, the virus is cleared from the cornea, which remains transparent and noninflamed. However, in CD4 T-cell-sufficient mice, a secondary infiltration of Th1 cells leads to a more chronic inflammation and scar tissue formation. While these pleiotropic Th1 cytokines undoubtedly regulate many aspects of HSK, those identified include IFN-γ upregulation of platelet/endothelial cell-adhesion molecule (PECAM) on blood vessels, which facilitates neutrophil infiltration of the cornea,[43] and indirect regulation by IL-2 of the migration and survival of neutrophils within the cornea.[44] The role of IL-12, a heterodimeric cytokine composed of p40 and p35 chains that promotes Th1 differentiation and IFN-γ production, is somewhat controversial in HSK..[45–47] A recent study showed HSK develops normally in mice deficient in the p40 chain, but is transient in mice deficient in the p35 chain, or deficient in both the p35 and p40 chain.[46] Since the p40 chain is a component of both IL-12 and IL-23 (an IL-12 family member that promotes the expansion of Th17 cells), these findings suggest that both IL-12 and IL-23 are dispensable for HSK progression, and a unique IL-12-independent role for the p35 chain in progression of HSK.

Other cytokines that contribute to HSK include TNF-α, IL-1, IL-6 and IL-17. TNF-α and IL-1 are involved in regulating the infiltration of T cells, neutrophils and MHC class II-positive DCs after infection with HSV-1.[48] Both cytokines may activate the local vascular endothelium to increase extravasation of these leukocytes. IL-6 can induce the expression of neutrophil-attracting chemokines, macrophage-inflammatory protein (MIP)-1α, IL-8, as well as MIP-3α, which attracts DCs.[49] IL-17 expression has been observed in human and mouse corneas with HSK, and the receptor for IL-17 is expressed constitutively on both human and mouse corneal fibroblasts.[50] In addition to inducing IL-6 expression, IL-17 stimulates matrix metalloproteinase-1 expression in fibroblasts. The expression of this enzyme may weaken the corneal collagen matrix, thus breaching the integrity of the cornea. IL-17 also induces the expression of neutrophil chemotactic and survival factors, such as IL-8 and granulocyte–macrophage colony-stimulating factor (GM-CSF).

Chemokines play a critical role not only in coordinating the innate immune response that leads to control of HSV-1 replication, but also in mediating the events that transpire in HSK. Upon stimulation by IL-1β and TNF-α, HSV-1-infected epithelial cells in the cornea express the chemokine CCL20.[51] CCL20 may be involved in the infiltration of DCs, which occurs when epithelial lesions develop, as well as during HSK development. It was also shown that IFN-γ-inducible protein (IP)-10, as well as monocyte chemotactic protein-1, may attract CD4 T cells into the cornea.[52] Conversely, IP-10 was observed to inhibit neovascularization,[53] a process that contributes significantly to HSV-1-mediated corneal inflammation, as discussed later.


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