The innate immune system in diabetic retinopathy

https://doi.org/10.1016/j.preteyeres.2021.100940Get rights and content

Abstract

The prevalence of diabetes has been rising steadily in the past half-century, along with the burden of its associated complications, including diabetic retinopathy (DR). DR is currently the most common cause of vision loss in working-age adults in the United States. Historically, DR has been diagnosed and classified clinically based on what is visible by fundoscopy; that is vasculature alterations. However, recent technological advances have confirmed pathology of the neuroretina prior to any detectable vascular changes. These, coupled with molecular studies, and the positive impact of anti-inflammatory therapeutics in DR patients have highlighted the central involvement of the innate immune system. Reminiscent of the systemic impact of diabetes, immune dysregulation has become increasingly identified as a key element of the pathophysiology of DR by interfering with normal homeostatic systems. This review uses the growing body of literature across various model systems to demonstrate the clear involvement of all three pillars of the immune system: immune-competent cells, mediators, and the complement system. It also demonstrates how the relative contribution of each of these requires more extensive analysis, including in human tissues over the continuum of disease progression. Finally, although this review demonstrates how the complex interactions of the immune system pose many more questions than answers, the intimately connected nature of the three pillars of the immune system may also point to possible new targets to reverse or even halt reverse retinopathy.

Introduction

Diabetes, characterized by the dysregulation of carbohydrate and lipid metabolism, results from impaired insulin secretion and/or insulin resistance. Its prevalence has more than quadrupled over the past four decades, from 108 million in 1980 to more than 425 million worldwide (Internation Diabetes Federation, 2019; World Health Organization, n.d.). This, coupled with one-third of all diabetic individuals experiencing related vision complications (Ko et al., 2012), has resulted in diabetic retinopathy (DR) becoming the leading cause of preventable vision loss in working-age individuals (Yau et al., 2012). DR has classically been viewed as a microvascular complication of diabetes and categorized based on those vascular abnormalities (Bursell et al., 2001; Treatment and Retinopathy, 1991a, 1991b, 1991c; Wilkinson et al., 2003). However, more recent discoveries of neurodegeneration and immune dysregulation early in DR patients have called into question this vascular-centric view (Kong et al., 2016). Consistent with these findings, inflammatory genes are most closely tied to DR, as identified by genome-wide association studies (Abhary et al., 2009).

The mechanisms behind these immune system–based manifestations in human DR patients have been investigated in rodent models of DR. However, no rodent model fully recapitulates the human presentation of DR (Olivares et al., 2017). This major limitation has driven investigators to use a combination of models to study different human manifestations of DR, including drug-induced (e.g., streptozocin), genetic (i.e. Akita [Ins2Akita], and leptin receptor deficient [db/db]), and non-diabetic injury–based (e.g., oxygen-induced retinopathy [OIR]; and ischemia/reperfusion) (Lai and Lo, 2013; Olivares et al., 2017) models. Interestingly, a common feature that has emerged from these disparate models is the central role of the innate immune system. This manuscript will examine our evolving understanding of DR from the perspective of these experimental in vivo models contextualized to human studies and in vitro data. In particular, we will focus on the role of the innate immune system in DR-related neurodegeneration and vasculopathy.

Section snippets

The intricacy of the ocular innate immune system

The retina is exquisitely sensitive to metabolic perturbations due to the combination of high metabolic demand and limited vascular supply (Dai et al., 2014; Joyal et al, 2016, 2018; Kooragayala et al., 2015). Importantly, the innate immune system, through its role as the early responder to environmental perturbations, maintains the homeostasis and visual function of this environment (Murakami et al., 2020). Much of this homeostasis is maintained and controlled by the innate immune system in a

The complex role of the immune response in the early stages of the disease: preclinical diabetic retinopathy

Preclinical DR begins when diabetes is initially diagnosed and lasts until the first vascular abnormalities are detected, which usually takes many years (Abcouwer and Gardner, 2014). In contrast to its historical categorization as a clinically silent phase, preclinical DR is a period of significant disease progression, primarily through immune dysregulation. Diabetes, like many other stress conditions, initiates the microglial immune response as part of its defense mechanism and “normal”

Mechanisms of preclinical diabetic retinopathy neurodegeneration

Before the presence of any detectable vascular abnormality, preclinical DR patients experience a number of visual dysfunctions measurable through psychophysical testing, including deficits in peripheral vision, night vision, color-hue discrimination, and contrast discrimination (Jackson and Barber, 2010; Trento et al., 2017; Wolff et al., 2015). These functional deficits have further been confirmed and localized by multifocal electroretinopathy to distinct retinal areas in preclinical DR

Diabetes, blood-retinal barrier, and the neurovascular unit

BRB breakdown is a hallmark event during preclinical DR (Miyamoto et al., 1999; Schröder et al., 1991) and was recently reviewed (Subauste, 2019). Briefly, during diabetes, macroglia secrete increasing amounts of VEGF, which compromises barrier integrity (Stone et al., 1995; Wang et al., 2010), in the context of amplified microglial activation and levels of pro-inflammatory mediators (Jo et al., 2019). In response to this environment, endothelial cells express cell adhesion molecules (CAMs),

Emergence of the role of the innate immune response in diabetic retinopathy progression

DR has long been classified as a microvascular disease with pathophysiology thought to coincide with vascular abnormalities. Certainly, vasculopathy does cause neurodegeneration, vision impairment, and immune dysregulation. However, as we have previously detailed, the innate immune response is an independent driver of DR pathology. Thus, as DR progresses to NPDR and PDR, it becomes more difficult to definitively define causation. Regardless, this section will focus on the role of the innate

Future directions and conclusions

Vision loss is a particularly devastating complication of diabetes. Treatment options remain dramatically limited, with the widely celebrated anti-VEGF therapies effective only in one-third to one-half of patients with vision-threatening stages of the disease (Bressler et al., 2014; Elman et al., 2010; Nguyen et al., 2010). Hence there is more than ever a clear need to develop new therapies that are more effective to preserve vision. This hinges on our understanding of the pathophysiology

Author statement

W.W.P. and P.E.F. wrote the manuscript. F.L. edited the manuscript. P.E.F. and F.L. obtained funding. The authors have declared that no conflict of interest exists.

Acknowledgements

This project and its authors were supported by NIH EY020895, the NIDDK, Eversight, the Juvenile Diabetes Research Foundation and the Thomas Beatson Foundation. This work utilized the Core Center for Vision Research funded by P30 EY007003 from the National Eye Institute. The authors are very grateful for the assistance of David Murrell in making the illustrations for this manuscript. Patrice E. Fort is the guarantor of this work. The authors declare having no conflicts of interests.

Glossary

BDNF
brain-derived neurotrophic factor
BRB
blood-retinal barrier
CAM
cell adhesion molecule
CX3CL1
fractalkine
CX3CR1
fractalkine receptor
db/db
leptin receptor deficient
DC
dendritic cell
DME
diabetic macular edema
DR
diabetic retinopathy
IL:
interleukin
MCP-1
monocyte chemoattractant protein-1
NPDR
non-proliferative diabetic retinopathy
NVU
neurovascular unit
OIR
oxygen-induced retinopathy
PDR
proliferative diabetic retinopathy
PEDF
pigment epithelium–derived factor
RPE
retinal pigment epithelium
TNFα
tumor necrosis factor α

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