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Bing Xu; Epithelium-expressed CXCL10 and Natural killer cells in protective corneal mucosal immunity against Candida albicans infection. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6258.
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We previously showed that pre-exposure of the cornea to flagellin induces profound mucosal innate protection against Candida (C.) albicans infection In this study, we sought to delineate the involvement of chemokine CXCL10 in this mucosal protection.
B6 mouse corneas were infected with C. albicans and progression of fungal keratitis was monitored by slit lamp microscopy and clinical scoring and by assessing fungal burden, neutrophil infiltration, and the expression of pro-inflammatory cytokine CXCL2. The effects of CXCL10 on fungal keratitis were assessed by antibody-mediated neutralization and by topical application of recombinant protein. CXCL10 targeted cells or CXCR3, the CXCL10 receptor, expressing cells, were identified by localization of CXCL10 or CXCR3 with antibodies specific for innate immune cells.
The expression of CXCL10 was stimulated by flagellin alone, greatly augmented at 6 h post infection (hpi), and suppressed at 24 hpi in B6 mouse corneas pretreated with flagellin. Neutralizing CXCL10 and CXCR3 increased keratitis severity and dampened flagellin induced protection, suggesting that CXCL10 through CXCR3 to exert its protective role in fungal keratitis. At cellular levels, flagellin- and/or C. albicans-induced CXCL10 was primarily found in epithelia at 0 and 6 hpi. At 24 hpi, epithelial cells expressed high levels of CXCL10 at lesion sites and CXCR3 positive cells were found in the epithelia and stroma whereas only a few CXCL10 and CXCR3 positive cells in flagellin-pretreated cornea. The majority of CXCR3-positive cells were NK1.1 positive which also expressed high level CXCL10 in infected corneas. These CXCR3 positive NK cells remained in C. albicans-free but inflammatory corneas for several days. Recombinant CXCL10 reduced C. albicans growth in vitro and accelerated fungal clearance and inflammation resolution, and prevented corneal neovascularization in vivo.
Epithelium-expressed CXCL10 plays a role in early stages of fungal clearance and CXCL10-/CXCR3-expressing NK cells, as part of innate defense apparatus, participated in the eradication of invading C. albicans in B6 mouse corneas.
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