title: Flagellin-induced expression of CXCL10 mediates direct fungal killing and recruitment of NK cells to the cornea in response to Candida albicans infection.
abstract: 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.
authors: Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors: Xiaowei
authors: X
authors: Liu
authors: Nan
authors: N
authors: Gao
authors: Chen
authors: C
authors: Dong
authors: Li
authors: L
authors: Zhou
authors: Qing-Sheng
authors: QS
authors: Mi
authors: Theodore J
authors: TJ
authors: Standiford
authors: Fu-Shin X
authors: FS
authors: Yu
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology*; D003315:Cornea / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005408:Flagellin / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D018928:Immunity, Mucosal / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007634:Keratitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011550:Pseudomonas aeruginosa / Q000737:chemistry*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D018398:Homeodomain Proteins; D054367:Receptors, CXCR3; D005408:Flagellin; C064658:RAG-1 protein
keywords: Antimicrobial peptides; CXCL10; Fungal keratitis; Innate immunity; Natural killer cells