title: Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush.
abstract: Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Yonju
authors.initials: Y
authors.lastname: Ha
authors.affiliation: Center for Biomedical Engineering, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Panpan
authors.initials: P
authors.lastname: Yi
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Jared
authors.initials: J
authors.lastname: Nathanson
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.affiliation: Department of Radiation Oncology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Bradford
authors.initials: B
authors.lastname: Loucas
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Jiaren
authors.initials: J
authors.lastname: Sun
authors.affiliation: College of Optometry, University of Houston, Houston, Texas.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Frishman
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas; Center for Biomedical Engineering, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamedi
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas. Electronic address: we2zhang@utmb.edu.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054357:Chemokine CXCL10 / Q000378:metabolism*; D004195:Disease Models, Animal; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D017404:In Situ Hybridization, Fluorescence; D036904:Leukocyte Rolling / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009409:Nerve Crush; D020221:Optic Nerve Injuries / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000473:pathology*
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3