The complement system is a component of the innate immune system consisting of >30 circulating systemic proteins associated with inflammation, opsonization, phagocytosis, and cell death. This system is activated via multiple pathways that converge at central complement factor C3:¹

• When the pathway is activated (by the accumulation of C1q from age and inflammation, for example), C3 and C5 convertases are formed.
• C3 is cleaved into pro-inflammatory anaphylatoxin C3a and opsonin C3b, initiating inflammation and phagocytosis. C3b activates the C5 convertase.
• Cleavage of complement factor C5 generates pro-inflammatory anaphylatoxin C5a and C5b.
• C5b recruits C6, C7, and C8 and ultimately forms a pore called the membrane attack complex (MAC) via polymerization with C9 molecules.
• When MAC accumulates beyond a certain threshold, disruption of the membrane and cell lysis occurs.

During the visual cycle, vitamin A (retinol) is moved across the retina (between the photoreceptors and the retinal pigment epithelium [RPE]) in its various isoforms:¹

• all-trans-retinol
• all-trans-retinyl esters
• all-trans-retinaldehyde
• 11-cis-retinol
• 11-cis-retinyl esters
• 11-cis-retinaldehyde
• retinoic acid

Vitamin A dimer by-products, such as N-retinylidene-N-retinylethanolamine (A2E), result when a portion of the retinaldehyde condenses with phosphatidylethanolamine (PE) to form retinaldehyde-PE.¹

Abnormal accumulation of toxic dimers causes damage and – ultimately – degeneration of the RPE.¹

Multiple factors can contribute to oxidative stress, including:¹

• Cigarette smoking
• Photoreceptor shedding
• Excessive light exposure
• Aging
• Increased Alu RNA (a mediator of ROS generation)

Increased oxidative stress at the intracellular level results in mitochondrial dysfunction due to:¹

• Mitochondrial DNA damage
• Oxidation of mitochondrial proteins and lipids
• Structural damage to the mitochondria

This leads to metabolic reprogramming, which has been shown to increase glycolytic metabolism of the RPE, resulting in RPE dysfunction and photoreceptor disruption.¹

Damage-associated molecular patterns (DAMPs) – such as A2E (a byproduct of the visual cycle), cholesterol, amyloid-ß, and lipofuscin – trigger MyD88 signaling and NFkB-induced transcription.¹

This leads to enhanced expression of NLRP3 and activation of the NLRP3 inflammasome.¹

Activation of the inflammasome causes elevated levels of IL-1ß and IL-18 (cytokines that mediate innate and adaptive immune pathways), ultimately resulting in inflammation and Caspase-mediated apoptosis.¹