The innate immune system in diabetic 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
References (326)
- et al.
The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited
Prog. Retin. Eye Res.
(2010) - et al.
Biochimica et Biophysica Acta Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice
BBA - Mol. Basis Dis.
(2016) - et al.
Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential
Prog. Retin. Eye Res.
(2004) - et al.
Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice
J. Biol. Chem.
(2010) - et al.
Vision-related function after ranibizumab treatment for diabetic macular edema: results from RIDE and RISE
Ophthalmology
(2014) - et al.
Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis
Am. J. Pathol.
(2002) - et al.
Stereo nonmydriatic digital-video color retinal imaging compared with Early Treatment Diabetic Retinopathy Study seven standard field 35-mm stereo color photos for determining level of diabetic retinopathy
Ophthalmology
(2001) - et al.
Monounsaturated oleic acid modulates autophagy flux and upregulates angiogenic factor production in human retinal pigment epithelial ARPE-19 cells
Life Sci.
(2020) - et al.
Immune regulation in the aging retina
Prog. Retin. Eye Res.
(2019) - et al.
Resveratrol exhibits an effect on attenuating retina inflammatory condition and damage of diabetic retinopathy via PON1
Exp. Eye Res.
(2019)
Stress, inflammation, and defense of homeostasis
Mol. Cell
Müller cells and diabetic retinopathy
Vis. Res.
Interleukin-6 (IL-6) mediates protection against glucose toxicity in human Müller cells via activation of VEGF-A signaling
Biochem. Biophys. Res. Commun.
One-year outcomes of the da VINCI study of VEGF trap-eye in eyes with diabetic macular edema
Ophthalmology
Hyperglycemia affects flicker-induced vasodilation in the retina of healthy subjects
Vis. Res.
Microglial cells in organotypic cultures of developing and adult mouse retina and their relationship with cell death
Exp. Eye Res.
Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema
Am. J. Ophthalmol.
Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy
Am. J. Pathol.
A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study
Ophthalmology
Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment
Ann. N. Y. Acad. Sci.
A systematic meta-analysis of genetic association studies for diabetic retinopathy
Diabetes
Expression of apoptosis markers in the retinas of human subjects with diabetes
Investig. Ophthalmol. Vis. Sci.
Modulation of retinal capillary endothelial cells by Müller glial cell-derived factors
Mol. Vis.
Retinal neuropathy precedes vasculopathy in diabetes: a function-based opportunity for early treatment intervention?
Clin. Exp. Optom.
Adeno-associated virus mediated delivery of a non-membrane targeted human soluble CD59 attenuates some aspects of diabetic retinopathy in mice
PloS One
Diabetic retinopathy and BDNF: a review on its molecular basis and clinical applications
J. Ophthalmol.
Intravitreal injection of adenosine A2A receptor antagonist reduces neuroinflammation, vascular leakage and cell death in the retina of diabetic mice
Sci. Rep.
Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury
Diabetologia
The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence
Science
Subtle thinning of retinal layers without overt vascular and inflammatory alterations in a rat model of prediabetes
Mol. Vis.
Interleukin 27 induces the expression of complement factor H ( CFH ) in the retina 7
Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy
Arch. Ophthalmol.
Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group
Eye
Bowman lecture 1998. Diabetic retinopathy: some cellular, molecular and therapeutic considerations
Eye
Claudin-5 redistribution induced by inflammation leads to anti-VEGF–resistant diabetic macular edema
Diabetes
A key role for ROCK in TNF-α-mediated diabetic microvascular damage
Investig. Ophthalmol. Vis. Sci.
Role of arginase 2 in murine retinopathy associated with western diet-induced obesity
J. Clin. Med.
TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability
Diabetes
Blocking CD200-CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats
Ocul. Immunol. Inflamm.
The Ins2Akita mouse as a model of early retinal complications in diabetes
Investig. Ophthalmol. Vis. Sci.
Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin
J. Clin. Invest.
p75NTR and its ligand ProNGF activate paracrine mechanisms etiological to the vascular, inflammatory, and neurodegenerative pathologies of diabetic retinopathy
J. Neurosci.
Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes
Invest. Ophthalmol. Vis. Sci.
Angiostatic role or astrocytes: suppression of vascular endothelial cell growth by TGF‐β and other inhibitory factor(s)
Glia
CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes
J. Mol. Med.
Axo-glial relations in the retina-optic nerve junction of the adult rat: freeze-fracture observations on axon membrane structure
J. Neurocytol.
Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy
Diabetologia
The db/db Mouse : a useful model for the study of diabetic retinal neurodegeneration 9
Assessment of neurotrophins and inflammatory mediators in vitreous of patients with diabetic retinopathy
Investig. Ophthalmol. Vis. Sci.
Oscillatory potential amplitudes: relation to severity of diabetic retinopathy
Arch. Ophthalmol.
Cited by (52)
Deep learning enabled hemorrhage detection in retina with DPFE and splat segmentation in fundus images
2024, Biomedical Signal Processing and ControlThe complement system and diabetic retinopathy
2024, Survey of OphthalmologyStudies of the retinal microcirculation using human donor eyes and high-resolution clinical imaging: Insights gained to guide future research in diabetic retinopathy
2023, Progress in Retinal and Eye ResearchCitation Excerpt :Several parallel pathogenic pathways define the pathogenesis of DR. However, there is some degree of overlap between these pathways. These pathways include: 1) Vasculogenic pathway; 2) Neurodegenerative pathway (Barber, 2003; Lieth et al., 2000; Sohn et al., 2016); 3) Immune-mediated and inflammatory pathways (Altmann and Schmidt, 2018; Joussen et al., 2004; Kern, 2007; Pan et al., 2021). A significant proportion of studies have examined each of these pathways in isolation and it has been difficult to discern if these pathways are indeed separate or if changes characterising one pathway is the cause/effect of changes due to another.
Single-cell RNA sequencing reveals roles of unique retinal microglia types in early diabetic retinopathy
2024, Diabetology and Metabolic SyndromeRole of complement protein regulatory targets in diabetic retinopathy and its clinical research progress
2024, International Eye ScienceMacrophage activation contributes to diabetic retinopathy
2024, Journal of Molecular Medicine
- 1
Percentage of work contributed by each author in the production of the manuscript is as follows: WWP 45%; FL 15%; PEF 40%.