Inhibition of connexin hemichannels protects retinal ganglion cells against ocular nerve injury
Yu Du, Jianping Zhang, Randolph Glickman, Daniel J Mojica, Ching-Kang Chen, Sumin Gu, Jean X Jiang
Abstract
Retinal ganglion cell (RGC) degeneration caused by optic nerve injury and diseases such as glaucoma leads to irreversible vision loss, yet effective neuroprotective treatments remain elusive. Secondary degeneration driven by astrocytic gliosis and neuroinflammation contributes substantially to neuronal death. Connexin 43 (Cx43), a gap junction protein abundantly expressed in astrocytes, is a key mediator of these secondary responses. Using an optic nerve crush (ONC) mouse model that recapitulates traumatic optic neuropathy, we found that Cx43 haploinsufficiency significantly preserved visual function, limited inner retina thinning, and protected RGCs from apoptosis and macrophage infiltration. Mechanistically, cytokine stimulation of astrocytes triggered Cx43 hemichannel opening and the release of inflammatory ATP and neurotoxic glutamate, which in turn promote RGC apoptosis. A novel Cx43(M1) antibody selectively inhibited astrocytic hemichannels, prevented the release of these factors, and reduced RGC death. Remarkably, a single administration of Cx43(M1) 30 min after ONC improved visual function and RGC survival for at least four weeks, accompanied by attenuated gliosis and reduced Cx43 expression. Together, these findings identify astrocytic Cx43 hemichannels as key mediators of secondary RGC neurodegeneration and demonstrate that their targeted inhibition confers sustained neuroprotection following optic nerve injury.