CXC chemokine receptor 2 but not C-C chemokine receptor 1 expression is essential for neutrophil recruitment to the cornea in helminth-mediated keratitis (river blindness).
Infiltration of neutrophils and eosinophils into the mammalian cornea can result in loss of corneal clarity and severe visual impairment. To identify mediators of granulocyte recruitment to the corneal stroma, we determined the relative contribution of chemokine receptors CXC chemokine receptor (CXCR)-2 (IL-8R homologue) and CCR1 using a murine model of ocular onchocerciasis (river blindness) in which neutrophils and eosinophils migrate from peripheral vessels to the central cornea. CXCR2(-/-) and CCR1(-/-) mice were immunized s.c. and injected into the corneal stroma with Ags from the parasitic helminth Onchocerca volvulus. We found that production of macrophage-inflammatory protein (MIP)-2, KC, and MIP-1 alpha was localized to the corneal stroma, rather than to the epithelium, which was consistent with the location of neutrophils in the cornea. CCR1 deficiency did not inhibit neutrophil or eosinophil infiltration to the cornea or development of corneal opacification. In marked contrast, neutrophil recruitment to the corneas of CXCR2(-/-) mice was significantly impaired (p < 0.0001 compared with control, BALB/c mice) with only occasional neutrophils detected in the central cornea. Furthermore, CXCR2(-/-) mice developed only mild corneal opacification compared with BALB/c mice. These differences were not due to impaired KC and MIP-2 production in the corneal stroma of CXCR2(-/-) mice, which was similar to BALB/c mice. Furthermore, although MIP-1 alpha production was lower in CXCR2(-/-) mice than BALB/c mice, eosinophil recruitment to the cornea was not impaired. These observations demonstrate the critical role for CXCR2 expression in neutrophil infiltration to the cornea and may indicate a target for immune intervention in neutrophil-mediated corneal inflammation.
Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA.
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Hall
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Diaconu
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Patel
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Pearlman
D000818:Animals; D000909:Antibodies, Helminth / Q000096:biosynthesis; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054407:Chemokine CCL4; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis / Q000378:metabolism*; D019743:Chemokines, CXC; D003315:Cornea / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D003318:Corneal Opacity / Q000235:genetics / Q000276:immunology / Q000469:parasitology; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D019573:Epithelium, Corneal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007634:Keratitis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D017181:Onchocerca volvulus / Q000276:immunology*; D015827:Onchocerciasis, Ocular / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology
D000909:Antibodies, Helminth; C515301:Ccr1 protein, mouse; D054407:Chemokine CCL4; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; C074302:keratinocyte-derived chemokines