The Roles of Peripheral Inflammation and the Complement System in Glaucoma

Abstract

Glaucoma is a group of neurodegenerative diseases of the eye that affect ganglion cells in the retina and without treatment lead to blindness. It is estimated that there are more than 60 million people afflicted with this condition in the world. The currently available therapies for glaucoma are not always effective and are associated with various side effects. Development of new therapies is dependent upon better understanding of the molecular mechanisms of glaucoma pathogenesis. Elevated intraocular pressure (IOP) is a major risk factor for development of glaucoma and its progression. However, a substantial proportion of patients with glaucoma has IOP values that fall within the normal range which indicates involvement of other factors in glaucomatous pathology. We hypothesized that peripheral inflammation may play a role in neuronal damage in glaucoma, as seen in some other chronic neurodegenerative disorders. We peripherally administered small amounts of bacterial lipopolysaccharide (LPS) to DBA/2J mice that develop optic neuropathy with characteristics similar to human glaucoma. We observed that such a challenge to the peripheral immune system significantly accelerated glaucomatous damage in this model in both the retina and the optic nerve two months after the treatment. At the same time, LPS treatment did not lead to glaucomatous pathology in other control strains of mice. The degree of peripheral inflammatory response to LPS, as well as LPS dosage, strongly influenced the amount of damage in this model. We investigated which molecular pathways and cellular changes could be responsible for this enhanced glaucomatous pathology. We observed significant upregulation of toll-like receptor 4 (TLR4) pathway genes as well as a critical component of the complement system, complement component C1q, following LPS administration. In addition, LPS-induced peripheral inflammation led to activation of microglial cells evident by increase in their numbers in the optic nerve (ON) head region and transition to an aggressive morphological state in the retina. By blocking the TLR4 pathway using a competitive inhibitor (naloxone), we were able to observe protection of retinal ganglion cells (RGC) in this model. We also investigated whether genetic knockout of C1q would protect DBA/2J mice from spontaneous glaucoma. We observed that C1q-deficient male mice were significantly protected from RGC loss at 12 months of age as compared to both wild-type mice and mice carrying a single C1q allele. Given the importance of complement activation in glaucoma we sought to understand how other factors besides peripheral inflammation, such as IOP elevation, could mediate changes in the expression of complement components in the retina. Our investigations revealed that short-term IOP elevations were not sufficient for complement activation in the retina. These studies provide novel insights into the mechanisms that are operating in glaucoma. Results from this work may help advance our understanding about the pathophysiology of the disease and may allow designing novel therapies as well as public health interventions.