The Role of the Complement System in Photoreceptor Cell Death during Retinal Detachment.

Abstract

Purpose : Photoreceptor loss is irreversible and is the primary cause of vision loss worldwide; understanding the mechanisms underlying photoreceptor cell death is critical to developing treatment strategies. The complement system is an intricate innate immune surveillance pathway that is able to discriminate between healthy host tissue, diseased host tissue, apoptotic cells and foreign invaders while modulating the elimination and repair of host tissue accordingly. We studied the role of the complement system facilitatine photoreceptor cell death in retinal detachment (RD).

Methods : We studied the innate immune system regulators in a well-defined mouse model of RD and using human vitreous of patients with RD. The mouse RD model allowed us to take advantage of the well-established genetic manipulation platforms in mice (e.g. complement deficient knock out strains). ELISA was used to measure complement levels in both human vitreous and detached mouse retina. RTPCR was used to measure complement activity. TUNEL staining was used to quantify dying cells in ONL of detached mouse retina. Hypoxyprobe^TM and electrode oxygen sensors were used to measure hypoxia in mouse retina. Data was analyzed using an unpaired Student t test.

Results : We found that in RD photoreceptors down-regulate membrane inhibitors of complement, Cd55 and Cd59, allowing for their selective targeting by the complement system. The detached retina becomes hypoxic causing up-regulation of the alternative complement pathway. This was found to promote early photoreceptor death. Preventing complement production using knockout mice or through pharmacologic inhibition, ameliorates much of the photoreceptor cell death observed in RD.

Conclusions : This study identified a new role for the alternative complement pathway in photoreceptor death in RD. Understanding the mechanism by which the innate immune system facilitates photoreceptor cell death will provide new therapeutic targets for this retinal condition and other neurodegenerative conditions.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.