Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy

Abstract

Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to determine the mechanisms associated with microglial activation and vascular leakage during diabetic retinopathy (DR) and under conditions of low-level endotoxemia, common in diabetic patients. Utilizing the Ins2Akita strain (Akita), a mouse model of type 1 diabetes, our results show that leakage of the blood-protein fibrin(ogen) into the retina occurs as a result of chronic (4 months) but not acute (1.5 months) hyperglycemia. Conversely, inducing endotoxin-mediated systemic inflammation during acute diabetes resulted in fibrinogen deposition in the retina, a phenotype that was exacerbated in mice lacking CX3CR1 signaling. Systemic inflammation in Cx3cr1−/− mice led to robust perivascular clustering of proliferating microglia in areas of fibrinogen extravasation, and induced IL-1β expression in microglia and astrocytes. Lastly, we determined a protective effect of modulating FKN/CX3CR1 signaling in the diabetic retina. We show that intravitreal (iv) administration of recombinant FKN into diabetic FKN-KO mice, reduced fibrinogen deposition and perivascular clustering of microglia in the retina during systemic inflammation. These data suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signaling disrupts the vascular integrity in retina during systemic inflammation.

PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB

“…58 Normal neurons in the central nervous system, as well as in the retina, constitutively express fractalkine. 59 Disruption of fractalkine signaling influences microglial physiology in disease conditions. 60 VEGF, as an important angiogenic factor, plays a role in several retinopathies, such as retinopathy of prematurity and diabetic retinopathy.…”

On phagocytes and macular degeneration

“…The increased expression of inflammatory cytokines leads to the recruitment of neurotoxic blood-derived iMϕs (CCL2), the resistance to subretinal MP clearance (IL-6), and photoreceptor toxicity (IL-1β) in Cx3cr1-deficient mice (see 4., 5.2.2.3, and 5.2.2.1. respectively) (Eandi et al, 2016;Hu et al, 2015;Sennlaub et al, 2013). Cx3cr1 deletion also increases MP accumulation and associated degenerative changes in other retinal disease models, such as diabetes (Beli et al, 2016;Cardona et al, 2015;Kezic et al, 2013;Mendiola et al, 2016), retinitis pigmentosa (Peng et al, 2014;Zabel and Kirsch, 2013),…”

“…signaling in AMD. In addition, in animal models, the injection of soluble CX3CL1 has been shown to restore tonic MP inhibition and curb pathogenic inflammation (Mendiola et al, 2016;Zabel and Kirsch, 2013) and might be useful to treat inflammation in patients.…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Inhibition of CC‐motif chemokine ligand 2 (CCL2) or IL‐1β also prevented inflammatory macrophage recruitment and photoreceptor degeneration in these animals (Sennlaub et al, ; Eandi et al, ). Conversely, positive modulation of CX3CL1–CX3CR1 signaling in the diabetic mouse retina by intravitreal administration of recombinant fractalkine effectively reduced microglial proliferation (Mendiola et al, ).…”