Gamma Interferon and Interleukin-1 Receptor 1 Regulate Neutrophil Recruitment to the Corneal Stroma in a Murine Model ofOnchocerca volvulusKeratitis

Abstract

Toll-like receptor 2 (TLR2) is an essential mediator of corneal inflammation induced by the filarial nematodeOnchocerca volvulus, which harbors endosymbioticWolbachiabacteria. TLR2 is also required for dendritic cell activation, gamma interferon (IFN-γ) production, and neutrophil recruitment to the cornea. To examine the role of IFN-γ inO. volvuluskeratitis, C57BL/6 and IFN-γ^−/−mice were immunized subcutaneously, and a soluble antigen extract fromO. volvulusadult worms (OvAg) was injected into the corneal stroma of each animal. We found that, in the absence of IFN-γ, neutrophil recruitment to the cornea was significantly impaired, whereas there was no effect on eosinophil infiltration. Since the cornea contains resident macrophages and fibroblasts and our previous studies showed that CXC chemokines mediate neutrophil recruitment, we examined the role of recombinant IFN-γ (rIFN-γ) on each cell type. We found no effect of rIFN-γ on CXC chemokine production by macrophages or corneal fibroblasts, either alone or with filarial extracts; in contrast, rIFN-γ was found to enhance OvAg-induced tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-1α, and IL-1β in macrophages. Furthermore, we found that rTNF-α, rIL-1α, or rIL-1β induced CXC chemokine production by corneal fibroblasts but not by macrophages. To determine the relative contributions of endogenous cytokines, we injected OvAg into the corneal stroma of C57BL/6, IL-1 receptor 1^−/−(IL-1R1^−/−), and TNF-αR1/2^−/−mice and examined neutrophil recruitment. We found that neutrophil infiltration was impaired in IL-1R1^−/−mice but not in TNF-αR1/2^−/−mice. IFN-γ therefore appears to regulate neutrophil recruitment to the corneal stroma by enhancing TLR2 expression and OvAg-induced IL-1α and IL-1β production by macrophages in the cornea, which then induce IL-1R1-dependent production of CXC chemokine by resident corneal fibroblasts.