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. (Am J Pathol 2017, 187: 352e365; http://dx

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AAV2-mediated GRP78 Transfer Alleviates Retinal Neuronal Injury by Downregulating ER Stress and Tau Oligomer Formation

“…The 488-nm laser was used for the excitation of green fluorescence, and a barrier filter at 500 nm was used to remove the reflected light with unchanged wavelength. 17 …”

“…ONC was used to induce TON as described. 17 Briefly, 4 to 5 weeks after AAV2 injection, mice were anesthetized by intraperitoneal injection of ketamine hydrochloride (100 mg/kg) and xylazine hydrochloride (10 mg/kg); 0.5 % proparacaine was applied to the eye for local anesthesia before the procedure. After cutting conjunctiva around the eye globe, the optic nerve of right eye close to its origin in the optic disc was crushed for 10 seconds using forceps (Dumont RS5005; Roboz, Gaithersburg, MD, USA).…”

“…Primary RGCs were isolated from wild-type (WT) mouse pups at postnatal day 4 to 5 as described previously. 17 Briefly, collected retinas were dissociated in a papain solution (15 U/mL) at 37°C for 15 minutes, and macrophages and microglial cells were removed by incubation with anti-macrophage antiserum. Nonadherent cells were incubated with mouse Thy-1.2 antibody (BD Biosciences) to isolate ganglion cells.…”