Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders

Abstract

Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.

Keywords: DAMPs; age-related macular degeneration; diabetic retinopathy; endophthalmitis; glaucoma; inherited retinal disorders; ischemic retinopathies; ocular cancer; proliferative vitreoretinopathy; uveitis.

Figure 1

Overview of the DAMPs activating the RAGE pathway. The receptor for advanced glycation end-products (RAGE) is a multi-ligand protein that integrates the immunoglobulin superfamily of receptors. RAGE recognizes a variety of DAMPs including S100, high mobility group box 1 protein (HMGB1), Amyloid beta (Aβ), and transcription factor A mitochondrial (TFAM). RAGE activation leads to downstream NFκB signaling and transcription of inflammatory factors.

Figure 2

Overview of DAMPs activating the toll-like receptor (TLR) pathways. TLRs recognize a variety of DAMPs. Defensin activates TLR1; biglycan, decorin, versican, LMW hyaluronan, S100, HSP, Aβ, histones, HMGB1, and ET-1 activate TLR2; biglycan, decorin, LMW hyaluronan, HS, fibronectin, tenascin-C, S100, HSP, uric acid, Aβ, histones, HMGB1, HMGN1, ET-1, defensins, granulysin, syndecan, and glypican are reported to activate TLR4; versican activates TLR6; RNA activates TLR3, 7 and 8; and DNA activates TLR9. When TLRs are stimulated by DAMPs they dimerize and recruit downstream adaptor molecules, such as myeloid differentiation primary-response protein 88 (MyD88), and TRIF-related adaptor molecule (TRAM), which directs downstream molecules, leading to the activation of signaling cascades that converge at the NFκB, activator protein 1 (AP1), and interferon response factors (IRFs).

Figure 3

Overview of DAMPs activating the NLRP3 inflammasome. The first step in the 2-step process involves activation and translocation of NFκB into the nucleus to regulate the transcription of the oligomerization-like receptor pyrin-domain-containing protein 3 (NLRP3) inflammasome genes. The second step is actuation of NLRP3 inflammasome mediated by (a) DAMPs such as biglycan, LMW hyaluronan, uric acid, and Aβ to release cathepsin from lysosomal degradation; (b) K+ efflux via P2X7 receptor activation by DAMPs such as biglycan, ATP, Aβ, and cathelicidin; and (c) CD44 activation by LMW hyaluronan caspase-1 signaling pathway leading to caspase-1 activity and the release of mature IL-1β.

Figure 4

Overview of DAMPS activating other pathways: (a) In CD14-dependent pathway, DAMPs such as biglycan, versican, HSP60, and HSP70 activate TLR2, whereas DAMPs such as biglycan, HSP60, HSP70, S100A8, and S100A9) activate TLR4 signaling. After TLRs become activated, they dimerize and recruit downstream adaptor molecules, such as myeloid differentiation primary-response protein 88 (MyD88), initiating downstream signaling cascades that converge at NFκB and AP1 and leading to the transcription of inflammatory factors; (b) in ILR1/ST2 signaling pathway, DAMPs such as IL-1α and IL-33 can signal through IL1R1/IL1RAP. IL-1 or IL-33 activate the heterodimeric signaling receptor complex formation of IL1R1/IL1RAP, which creates the scaffold for MyD88 dimerization converging to NFκB pathway; (c) in CD91 signaling pathway, DAMPs such as calreticulin, HSP60, and HSP70 interact with CD91, which leads to endocytosis of calreticulin or HSPs and proteosome degradation, and cross-presentation of the chaperoned antigens culminating in co-stimulation of T cells; (d) in DNGR1 signaling pathway, F-actin interacts with DNGR1, which signals through the spleen tyrosine kinase (SYK), diverting phagocytosed cargo toward endosomal compartments, leading to cross-presentation and generation of resident memory CD8+ T cells.