The Role of Inflammation in Diabetic Retinopathy

Abstract

Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5⁺CD11b⁺ monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

Keywords: diabetes; inflammation; leukostasis; metabolic syndrome; obesity; protein tyrosine phosphatase 1B; retinopathy.

Figure 1

Model of PTP regulation of central leptin and insulin signaling. When circulating leptin binds to its receptor LepRb, the associated tyrosine kinase JAK2 autophosphorylates and phosphorylates specific tyrosine residues along the intracellular tail of the LepRb. Phosphorylation of Y985 allows for recruitment of the PTP SHP2 which mediates downstream ERK1/2 signaling, while phosphorylation of Y1138 allows for activation of STAT3 which regulates transcription of key neuropeptides involved in energy homeostasis. Unlike leptin signaling, insulin binding to its receptor results in receptor autophosphorylation at tyrosine residues 1158, 1162, and 1163. This allows for recruitment of the effector IRS, which upon phosphorylation can recruit adaptor molecules and mediate downstream PI3K and ERK1/2 signaling. In contrast to SHP2 which positively regulates leptin signaling, several PTPs can negatively regulate central leptin and insulin signaling. PTP1B inhibits leptin and insulin signaling by dephosphorylating JAK2 and the IR, respectively. Additionally, PTP1B has been implicated in dephosphorylating the downstream leptin/insulin signaling protein Tub. Like PTP1B, RPTPe has been shown to inhibit leptin signaling at the level of JAK2, while TCPTP negatively regulates leptin signaling via dephosphorylation of STAT3. PTEN antagonizes neuronal insulin-induced PI3K signaling via dephosphorylation of the phospholipid PIP3 into PIP2, resulting in decreased K+ ATP channel conductance [from Tsou and Bence (42)]. Figure created with Biorender.com.

Figure 2

Metabolic reprogramming in macrophage polarization. LPS and IFN-γ induce M1 macrophages. Metabolism in M1 macrophages is characterized by increased glycolysis and PPP activity, and a broken TCA cycle that leads to metabolite accumulation. M2 macrophages display a more oxidative metabolic profile, with a high reliance on the TCA cycle, utilizing OXPHOS and exhibiting high levels of FAO. Inhibition of glycolysis by 2-DG leads to an oxidative M2 phenotype [from Corcoran and O’Neill (48)]. Figure created with Biorender.com. * PKM2: pyruvate kinase M2.

Figure 3

Tank-binding protein kinase 1 (TBK1) operates at the intersection of energy expenditure and inflammation. For instance, TBK1 deficiency attenuates HFD-induced obesity but exaggerates inflammation through its effects on NF-kB–inducing kinase (NIK). TBK1 represses energy expenditure by phosphorylating and inhibiting AMPK and to the serine-threonine kinase Unc-51-Like Autophagy Activating Kinase 1 (ULK1). The combined effects of TBK1 are to attenuate NF-kB activation and mediate the anti-inflammatory effect of AMPK [from Zhao et al. (58)].

Figure 4

Activation of the cGAS-cGAMP-STING pathway mediates obesity-induced inflammation and metabolic disorders. Obesity reduces the expression levels of disulfide bond A oxidoreductase like protein (DsbA-L) in adipose tissue, leading to mitochondrial stress and subsequent mtDNA release into the cytosol. Aberrant localization of mtDNA in the cytosol activates the cGAS-cGAMPSTING pathway, leading to enhanced inflammatory gene expression and insulin resistance. Phosphorylated and activated TBK1 exerts a feedback inhibitory role by promoting STING ubiquitination and degradation or stimulating phosphorylation-dependent degradation of NF-kB–inducing kinase (NIK), thus attenuating cGAS-cGAMP STING–mediated inflammatory response [from Bai and Liu (80)]. Figure created with Biorender.com.

Figure 5

Retinal fundus images of diabetic retinopathy. (a) fundus photograph showing microaneurysms (arrows); (b) late fluorescein angiogram showing numerous microaneurysms (white dots) with small surrounding dark patches indicating focal retinal ischemia; (c) late fluorescein angiogram showing abnormal capillary permeability as small areas of diffuse dye leakage from microaneurysms (yellow arrows) surrounding a large dark, non-perfused patch of retinal ischemia (white arrow); (d) ultrawide field fundus image showing optic nerve head (yellow arrow), intraretinal microvascular abnormality (blue arrow) and pre-retinal haemorrhage (white arrow) (112).

Figure 6

(a) Optical coherence tomography (OCT) images of diabetic macular oedema: fundus image to indicate plane of “optical section” (red arrow) through the retina showing macular oedema/retinal cysts (white arrows) in image on the right; (c) ultrawide angle, pre-surgical image of pre-retinal (subhyaloid) haemorrhage in the vitreous cavity obscuring the optic nerve and macula; (c) post-surgical view of same eye in (b): vitreous cavity is now clear and optic nerve head (white arrow) and macula (yellow arrow) are visible.

Figure 7

Diagrams of retinal circulation: (A) normal blood flow from arterioles (red) through capillary network to venules; (B) abnormal blood flow in diabetic retinopathy showing microaneurysms, capillary loss (drop-out), retinal ischemia and venous beading.

Figure 8

Diagram of ischemic retina: (A) area of ischemia and oedema; (B) representation of tissue fibrin deposition and macrophage infiltration surrounding non-flowing venule.

Figure 9

Diabetes, The Metabolic Syndrome and Retinopathy. Diabetes caused by nutrient overload or autoimmune disease leads to beta cell dysfunction/loss inducing a chronic pro-inflammatory state in which leukocyte activation promotes early microvascular disease. This causes secondary tissue damage (retinopathy, nephropathy, and peripheral neuropathy). Direct damage to the tissues by chronic glycolipid toxicity develops more slowly compounding the pathological changes.