Flagellin-induced expression of CXCL10 mediates direct fungal killing and recruitment of NK cells to the cornea in response to Candida albicans infection.
We previously showed that topical flagellin induces profound mucosal innate protection in the cornea against microbial infection, a response involving multiple genes and cell types. In this study, we used a Candida albicans (CA)-C57BL/6 mouse keratitis model to delineate the contribution of CXCL10- and CXCR3-expressing cells in flagellin-induced protection. Flagellin pretreatment markedly enhanced CXCL10 expression at 6 h post CA infection (hpi), but significantly dampened CXCL10 expression at 24 hpi. At the cellular level, CXCL10 was expressed in the epithelia at 6 hpi in flagellin-pretreated corneas, and concentrated at lesion sites 24 hpi. CXCR3-expressing cells were detected in great numbers at 24 hpi, organized within clusters at the lesion sites in CA-infected corneas. CXCL10 or CXCR3 neutralization increased keratitis severity and dampened flagellin-induced protection. CXCR3-positive cells were identified as NK cells, the depletion of which resulted in severe CA keratitis. Contributions from NK T-cells were excluded by finding no change in flagellin-induced protection in Rag1 KO mice. Recombinant CXCL10 inhibited CA growth in vitro and accelerated fungal clearance and inflammation resolution in vivo. Taken together, our data indicate that epithelium-expressed CXCL10 plays a critical role in fungal clearance and that CXCR3-expressing NK cells contribute to CA eradication in mouse corneas.
['Liu|Xiaowei|X|', 'Gao|Nan|N|', 'Dong|Chen|C|', 'Zhou|Li|L|', 'Mi|Qing-Sheng|QS|', 'Standiford|Theodore J|TJ|', 'Yu|Fu-Shin X|FS|']
D000818:Animals D002176:Candida albicans D002177:Candidiasis D054357:Chemokine CXCL10 D003315:Cornea D005408:Flagellin D005786:Gene Expression Regulation D018398:Homeodomain Proteins D007111:Immunity, Cellular D018928:Immunity, Mucosal D007634:Keratitis D007694:Killer Cells, Natural D051379:Mice D018345:Mice, Knockout D011550:Pseudomonas aeruginosa D054367:Receptors, CXCR3
CXCL10 Antimicrobial peptides Fungal keratitis Innate immunity Natural killer cells