Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-05, Vol.114 (19), p.E3839-E3848
• Main Authors: Harder, Jeffrey M., Braine, Catherine E., Williams, Pete A., Zhu, Xianjun, MacNicoll, Katharine H., Sousa, Gregory L., Buchanan, Rebecca A., Smith, Richard S., Libby, Richard T., Howell, Gareth R., John, Simon W. M.
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Biological Sciences; Complement; Complement C3 - genetics; Complement C3 - immunology; Complement component C1q; Complement component C3; Elevation; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - immunology; Eye (anatomy); Glaucoma; Glaucoma - genetics; Glaucoma - immunology; Glaucoma - pathology; Glaucoma - prevention & control; Immune response; Immune system; Intraocular pressure; Intraocular Pressure - immunology; Medical treatment; Mice; Mice, Inbred DBA; Mice, Knockout; Optic nerve; Optic Nerve - immunology; Optic Nerve - pathology; PNAS Plus; Quinazolines - pharmacology; Retina; Retinal ganglion cells; Retinal Ganglion Cells - immunology; Retinal Ganglion Cells - pathology; Rodents; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Transcription; Tyrphostins - pharmacology; Up-Regulation - immunology; Wld protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1608769114

Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wlds allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wlds mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wlds mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/2J.Wlds mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.