Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.
Highlights
Aberrant inflammatory pathways constitute a major underlying mechanism in the perpetuation of several ocular diseases, including diabetic retinopathy (DR) [1,2]
In a type 2 diabetic model, rats fed a high-fat diet for ten weeks showed increased NLRP3 in the whole retina, which was later found to immunoprecipitate with thioredoxin-interacting protein (TXNIP) in human retinal endothelial cells [113]
Using a human brain microglial cell line (HMC3), we found microglial cells to constitutively express NOD1, NLRC5, NLRX, NLRP1, NLRP3, NLRP6, NLRP7, and NLRP10 (Figure 3)
Summary
Aberrant inflammatory pathways constitute a major underlying mechanism in the perpetuation of several ocular diseases, including diabetic retinopathy (DR) [1,2]. Multiple drugs targeting other systems involved in DR progression are being tested currently for better management of the disease [34] Their limited success urges the need for a more in-depth understanding of molecular pathways, which could exacerbate inflammation during DR [35]. Due to their numerous members and various structures, NLRs are versatile and participate in diverse biological processes They are involved in innate and adaptive immunity via regulation of antigen presentation and differentiation of the adaptive immune response; host defense mechanism via recognition of pathogen-associated molecular patterns (PAMPS); inflammation modulation via signal transduction through nuclear factor-kappa B (NF-κB) and formation of inflammasome; regulation of cell death by monitoring metabolic sensors and damage-associated molecular patterns (DAMPS). Inflammasomes are of particular interest in ocular diseases due to their involvement in inflammatory pathways These large protein complexes comprise of an NLR, an adaptor, and a recruited caspase-1. Unique localization and activation of NLRs in different retinal cell types and their function needs further studies for an accurate depiction of retinal diseases
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